Extended release pharmaceutical formulation and methods of treatment

ABSTRACT

The invention provides an oral extended release formulation for the treatment of treatment-resistant depression, treatment-resistant anxiety, and phobia.

This application is a Continuation of U.S. Ser. No. 16/754,389, filedMay 7, 2020, which claims the benefit under 35 U.S.C. § 371 ofInternational Application PCT/M2018/057851 filed on Oct. 10, 2018 whichis a continuation-in-part of and claims the benefit under 35 U.S.C. §120 of U.S. Ser. No. 15/728,695 (now U.S. Pat. No. 10,441,544) filed onOct. 10, 2017. International Application PCT/M2018/057851 filed on Oct.10, 2018 also in turn claims priority under 35 U.S.C. § 119(e) of U.S.Ser. No. 62/695,966 filed on Jul. 10, 2018. All of the foregoingapplications are incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

The initial report that low doses of the NMDA antagonist ketamine hadrapid onset antidepressant effects in patients with treatment resistantdepression (TRD; Berman 2000) has been confirmed in multiple subsequentstudies (Xu 2016). More recently ketamine has been shown to have similarrapid-onset activity in a range of treatment-resistant anxiety (TRA)disorders including Post-Traumatic Stress Disorder (PTSD; Feder 2014),Obsessive Compulsive Disorder (OCD; Rodriguez 2013), Generalized AnxietyDisorder (GAD) and Social Anxiety Disorder (SAD; Glue 2017). All ofthese studies have used injected ketamine, usually given intravenously.There are preliminary case series data suggesting that oral ketamine hasantidepressant effects in patients with TRD (Schoevers 2016). The majorside effects of injected ketamine include dissociative symptoms thatoccur mainly in the first hour after dosing, and minor increases inblood pressure and heart rate, which occur in the first 30 minutes. Anoral ketamine formulation could minimize these side effects, and be lessonerous/time consuming to administer than injected ketamine.

To explore the potential for an oral ketamine formulation to showactivity in patients with TRD or TRA, and/or who may suffer fromphobias, the inventors developed an extended release ketamine tablet,using a hydrophilic polymeric matrix approach. Polyethylene oxide (PEO)is one of a number of hydrophilic polymers used in controlled drugdelivery formulations, and has a number of positive attributes includingnontoxicity, high water solubility and swellability (Maggi 2002).Furthermore, tablets formulations based on a high concentration of PEOare able to be annealed (heated) to give tablets of very high hardnessthat are resistant to crushing. This is a particularly attractiveproduct attribute because ketamine is a drug of abuse. To minimize thepotential for dissociative symptoms associated with rapid absorption ofketamine, a prolonged release profile was desirable. The formulationdemonstrated linear in vitro dissolution over 10-12 hours. Eliminationhalf-life estimates for ketamine and norketamine for this formulationare much longer that previously reported for tablets.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY OF THE INVENTION

The invention provides a solid, oral, extended release pharmaceuticaltablet comprising: (A) a core comprising: i) a therapeutically effectiveamount of an active agent selected from the group consisting ofketamine, norketamine, pharmaceutically acceptable salts thereof, andcombinations thereof; ii) at least one high molecular weightpolyethylene oxide (PEO) that is cured, wherein said high molecularweight PEO has an approximate molecular weight of from about 2 millionto about 7 million, based upon rheological measurements, and is presentin an amount of at least about 30% (by weight) of the core; (B) acoating on said core, wherein said tablet is crush resistant and has abreaking strength of at least about 200 N; and provides a mean t_(max)of said active agent at least about 4 hours after administration of asingle tablet to a patient.

The invention provides a tablet wherein the molecular weight of saidhigh molecular weight PEO is selected from the group consisting of atleast about 4,000,000; at least about 5,000,000; at least about6,000,000; and at least about 7,000,000. The invention provides a tabletwherein the active agent comprises at least about 1% (by weight) of thecore. The invention provides a tablet wherein said high molecular weightPEO comprises at least about 50% (by weight) of said core. The inventionprovides a tablet wherein the dosage amount of active agent is selectedfrom the group consisting of about 30 mg, about 60 mg, about 120 mg, andabout 240 mg. The invention provides a tablet wherein the tablet iscured at a temperature of about 70° C. to about 75° C. The inventionprovides a tablet wherein the coating comprises: i)hydroxypropylmethylcellulose; ii) titanium dioxide; and iii)polyethylene glycol. The invention provides a tablet wherein said tabletprovides a ketamine C_(max) between about 12 and about 42 ng/mL. Theinvention provides a tablet wherein said tablet provides a ketamineAUC_(0-inf) between about 79 and about 385 ng·h/mL. The inventionprovides a tablet wherein said tablet provides a norketamine C_(max)between about 74 and about 315 ng/mL. The invention provides a tabletwherein said tablet provides a norketamine AUC_(0-inf) between about 872and about 4079 ng·h/mL. The invention provides a tablet wherein the meant_(max) of said active agent is selected from the group consisting of atleast about 4 hours, at least about 6 hours, at least about 8 hours, atleast about 10 hours, at least about 11 hours, and at least about 12hours. The invention provides a tablet wherein the tablet is suitablefor once daily administration or twice-daily administration to apatient. The invention provides a tablet wherein the tablet has no orminimal dissociative side effects upon administration to a patient.

The invention provides a method of treating a patient fortreatment-resistant depression, comprising: selecting a patient in needof such treatment; and orally administering to the patient a tabletcomprising: (A) a core comprising: i) a therapeutically effective amountof an active agent selected from the group consisting of ketamine,norketamine, pharmaceutically acceptable salts thereof, and combinationsthereof; ii) at least one high molecular weight polyethylene oxide (PEO)that is cured, wherein said high molecular weight PEO has an approximatemolecular weight of from about 2 million to about 7 million, based uponrheological measurements, and is present in an amount of at least about30% (by weight) of the core; (B) a coating on said core, wherein saidtablet is crush resistant and has a breaking strength of at least about200 N; and provides a mean t_(max) of said active agent at least about 4hours after administration of a single tablet to a patient, wherein thetablet treats the symptoms of said treatment-resistant depression.

The invention provides a method wherein the molecular weight of saidhigh molecular weight PEO is selected from the group consisting of atleast about 2,000,000, at least about 4,000,000; at least about5,000,000; at least about 6,000,000; and at least about 7,000,000. Theinvention provides a method wherein the active agent comprises at leastabout 1% (by weight) of the core. The invention provides a methodwherein said high molecular weight PEO comprises at least about 50% (byweight) of said core. The invention provides a method wherein the dosageamount of active agent is selected from the group consisting of about 1mg, about 2 mg, about 5 mg, about 10 mg, about 30 mg, about 60 mg, about120 mg, and about 240 mg. 20. The invention provides a method whereinthe tablet is cured at a temperature of about 70° C. to about 75° C. Theinvention provides a method wherein the coating comprises: i)hydroxypropylmethylcellulose; ii) titanium dioxide; and iii)polyethylene glycol. The invention provides a method wherein said tabletprovides a ketamine C_(max) between about 12 and about 42 ng/mL. Theinvention provides a method wherein said tablet provides a ketamineAUC_(0-inf) between about 79 and about 385 ng·h/mL. The inventionprovides a method wherein said tablet provides a norketamine C_(max)between about 74 and about 315 ng/mL. The invention provides a methodwherein said tablet provides a norketamine AUC_(0-inf) between about 872and about 4079 ng·h/mL. The invention provides a method wherein the meant_(max) of said active agent is selected from the group consisting of atleast about 4 hours, at least about 6 hours, at least about 8 hours, atleast about 10 hours, at least about 11 hours, and at least about 12hours. The invention provides a method wherein the tablet is suitablefor once daily administration or twice-daily administration to apatient. The invention provides a method wherein the symptoms of saidtreatment-resistant depression are alleviated within 2 hours of oraladministration of said ketamine. The invention provides a method whereinsaid method comprises oral administration of a single dose of saidketamine. The invention provides a method wherein said method comprisesoral administration of multiple doses of said ketamine. The inventionprovides a method wherein a single oral administration of said ketaminein doses between 30-180 mg is sufficient to alleviate the effects ofsaid depression for 3-7 days. The invention provides a method whereintablet has no or minimal dissociative side effects in the patient. Theinvention provides a method wherein maximal mean improvements in ratingsof depressed mood were noted after approximately 6 weeks of maintenancetreatment. The invention provides a method further comprisingadministering a pharmaceutically effective dose of a second oradditional agent, wherein said second or additional agent hasantidepressant properties.

The invention provides a method wherein said method further comprises anadditional therapy selected from: at least one antidepressant selectedfrom the group consisting of citalopram, escitalopram oxalate,fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxineand duloxetine; harmaline, iproniazid, isocarboxazid, nialamide,pargyline, phenelzine, selegiline, toloxatone, tranylcypromine,brofaromine, moclobemide; amitriptyline, amoxapine, butriptyline,clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine,iprindole, lofepramine, melitracen, nortriptyline, opipramol,protriptyline, trimipramine; maprotiline, mianserin, nefazodone,trazodone, pharmaceutically acceptable salts, isomers, and combinationsthereof; at least one mood stabilizer selected from the group consistingof lithium carbonate, lithium orotate, lithium salt, valproic acid,divalproex sodium, sodium valproate, lamotrigine, carbamazepine,gabapentin, oxcarbazepine, topiramate, pharmaceutically acceptablesalts, isomers, and combinations thereof, at least one herbalantidepressants selected from the group consisting of St John's Wort,kava kava, echinacea, saw palmetto, holy basil valerian, milk thistle,Siberian ginseng, Korean ginseng, ashwagandha root, nettle, Ginkgobiloba, gotu kola, ginkgo/gotu kola supreme, astragalus, goldenseal,dong quai, ginseng, St. John's wort supreme, echinacea, bilberry, greentea, hawthorne, ginger, gingko, turmeric, boswellia serata, blackcohosh, cats claw, catnip, chamomile, dandelion, chaste tree berry,black elderberry, feverfew, garlic, horse chestnut, licorice, red cloverblossom and leaf Rhodiola rusa, Coleus forskohlii, Passion Flower,eyebright, yohimbe, blueberry plant, black pepper plant, Hydrocotyleasiatica, astragalus, valerian poppy root and grape seed, vervain,echinacea ang root, Skull Cap, serenity elixir, and combinationsthereof, at least one antipsychotic agent selected from the groupconsisting of haloperidol, chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,promazine, triflupromazine, levomepromazine, promethazine,chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine,olanzapine, risperidone, quetiapine, ziprasidone, amisulpride,paliperidone, dopamine, bifeprunox, norclozapine, aripiprazole,tetrabenazine, cannabidiol, pharmaceutically acceptable salts, isomers,and combinations thereof; other therapeutic interventions selected fromthe group consisting of counseling, psychotherapy, cognitive therapy,electroconvulsive therapy, hydrotherapy, hyperbaric oxygen therapy,electrotherapy and electrical stimulation, transcutaneous electricalnerve stimulation (“TENS”), deep brain stimulation, vagus nervestimulation, and transcranial magnetic stimulation, and combinationsthereof.

The invention provides a method of treating a patient fortreatment-resistant anxiety, including but not limited to DSM-VGeneralized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder,Post-Traumatic Stress Disorder and/or Obsessive-Compulsive Disorder,comprising: selecting a patient in need of such treatment; and orallyadministering to the patient a tablet comprising: (A) a core comprising:i) a therapeutically effective amount of an active agent selected fromthe group consisting of ketamine, norketamine, pharmaceuticallyacceptable salts thereof, and combinations thereof; ii) at least onehigh molecular weight polyethylene oxide (PEO) that is cured, whereinsaid high molecular weight PEO has an approximate molecular weight offrom about 2 million to about 7 million, based upon rheologicalmeasurements, and is present in an amount of at least about 30% (byweight) of the core; (B) a coating on said core, wherein said tablet iscrush resistant and has a breaking strength of at least about 200 N; andprovides a mean t_(max) of said active agent at least about 4 hoursafter administration of a single tablet to a patient, wherein the tablettreats the symptoms of said treatment-resistant anxiety. The inventionprovides a method wherein the molecular weight of said high molecularweight PEO is selected from the group consisting of at least about2,000,000, at least about 4,000,000; at least about 5,000,000; at leastabout 6,000,000; and at least about 7,000,000. The invention provides amethod wherein the active agent comprises at least about 1% (by weight)of the core. The invention provides a method wherein said high molecularweight PEO comprises at least about 50% (by weight) of said core. Theinvention provides a method wherein the dosage amount of active agent isselected from the group consisting of about 1 mg, about 2 mg, about 5mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, and about 240mg. The invention provides a method wherein the tablet is cured at atemperature of about 70° C. to about 75° C. The invention provides amethod wherein the coating comprises: i) hydroxypropylmethylcellulose;ii) titanium dioxide; and iii) polyethylene glycol. The inventionprovides a method wherein said tablet provides a ketamine C_(max)between about 12 and about 42 ng/mL. The invention provides a methodwherein said tablet provides a ketamine AUC_(0-inf) between about 79 andabout 385 ng·h/mL. The invention provides a method wherein said tabletprovides a norketamine C_(max) between about 74 and about 315 ng/mL. Theinvention provides a method wherein said tablet provides a norketamineAUC_(0-inf) between about 872 and about 4079 ng·h/mL. The inventionprovides a method wherein the mean t_(max) of said active agent isselected from the group consisting of at least about 4 hours, at leastabout 6 hours, at least about 8 hours, at least about 10 hours, at leastabout 11 hours, and at least about 12 hours. The invention provides amethod wherein the tablet is suitable for once daily administration ortwice-daily administration to a patient. The invention provides a methodwherein the tablet has no or minimal dissociative side effects uponadministration to a patient. The invention provides a method wherein thesymptoms of said treatment-resistant anxiety are alleviated within 2hours of oral administration of said ketamine. The invention provides amethod wherein said method comprises oral administration of a singledose of said ketamine. The invention provides a method wherein saidmethod comprises oral administration of multiple doses of said ketamine.The invention provides a method wherein a single oral administration ofsaid ketamine in doses between 30-180 mg is sufficient to alleviate theeffects of said anxiety for 3-7 days. The invention provides a methodwherein maximal mean improvements in ratings of anxious mood were notedafter approximately 2 weeks of maintenance treatment. The inventionprovides a method further comprising administering a pharmaceuticallyeffective dose of a second or additional agent, wherein said second oradditional agent is has antianxiety properties. The invention provides amethod which further comprises an additional therapy selected from: atleast one antidepressant selected from the group consisting ofcitalopram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine,sertraline, dapoxetine, venlafaxine and duloxetine, harmaline,iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline,toloxatone, tranylcypromine, brofaromine, moclobemide, amitriptyline,amoxapine, butriptyline, clomipramine, desipramine, dibenzepin,dothiepin, doxepin, imipramine, iprindole, lofepramine, melitracen,nortriptyline, opipramol, protriptyline, trimipramine, maprotiline,mianserin, nefazodone, trazodone, pharmaceutically acceptable salts,isomers, and combinations thereof, at least one serotonin 1a partialagonist selected from the group consisting of buspirone, eltoprazine, ortandospirone, pharmaceutically acceptable salts, isomers, andcombinations thereof; at least one alpha-2-delta ligand selected fromthe group consisting of gabapentin, pregabalin, 3-methylgabapentin,(1alpha,3 alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoicacid, (3S,5R)-3 amino-5 methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantiadrenergic agents selected from the group consisting of clonidine,prazosin, propranolol, fuanfacine, methyldopa, guanabenz, doxazosin,prazosin, terazosin, silodosin, alfuzosin, tamsulosin,dutasertide/tamsulosin, guanadrel, mecemylamine, guanethidine,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one benzodiazepine agent selected from the group consisting ofalprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam,clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam,nimetazepam, estazolam, flunitrazepam, oxazepam, triazolam,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one antipsychotic agent selected from the group consisting ofhaloperidol, chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,promazine, triflupromazine, levomepromazine, promethazine,chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine,olanzapine, risperidone, quetiapine, ziprasidone, amisulpride,paliperidone, dopamine, bifeprunox, norclozapine, aripiprazole,tetrabenazine, cannabidiol, pharmaceutically acceptable salts, isomers,and combinations thereof; other therapeutic interventions selected fromthe group consisting of counseling, psychotherapy, cognitive therapy,electroconvulsive therapy, hydrotherapy, hyperbaric oxygen therapy,electrotherapy and electrical stimulation, transcutaneous electricalnerve stimulation (“TENS”), deep brain stimulation, vagus nervestimulation, and transcranial magnetic stimulation, and combinationsthereof.

The invention provides a method of treating a patient for DSM-5 SpecificPhobia, the method comprising the steps of: selecting a patient in needof such treatment; and administering ketamine to the patient in a dosageform selected from the group consisting of a subcutaneous injection, anintramuscular injection, an intravenous infusion, a controlled releasetablet, a lozenge, a sublingual formulation, an intranasal spray,combinations thereof, and any other effective route of administration.The invention provides a method wherein the dosage amount of ketamine isselected from the group consisting of about 1 mg, about 2 mg, about 5mg, about 10 mg, about 30 mg, about 60 mg, about 120 mg, and about 240mg. The invention provides a method wherein the dosing frequency of theketamine formulation ranges from once weekly, twice weekly, three timesweekly, up to daily administration to a patient. The invention providesa method wherein the DSM-5 Specific Phobia is selected from the groupconsisting of environmental phobia, animal phobia, situational phobia,bodily phobia, and combinations thereof. The invention provides a methodwherein the environmental phobia is selected from the group consistingof fear of germs, deep water, heights, and other environmental phobias,and combinations thereof. The invention provides a method wherein theanimal phobia is selected from the group consisting of fear of dogs,spiders, snakes, other animal phobias, and combinations thereof. Theinvention provides a method wherein the situational phobia is selectedfrom the group consisting of fear of flying in an aeroplane, visitingthe dentist, other situational phobias, and combinations thereof. Theinvention provides a method wherein the bodily phobia is selected fromthe group consisting of fear of blood exposure, other bodily phobias,and combinations thereof. The invention provides a method wherein thesymptoms of said specific phobia are alleviated within 1-3 hours ofadministration of said ketamine formulations. The invention provides amethod wherein said method comprises single dose administration of saidketamine formulations. The invention provides a method wherein saidmethod comprises multiple dose administrations of said ketamineformulations. The invention provides a method wherein a singleadministration of said ketamine formulations in doses between 30-180 mgis sufficient to alleviate the effects of said phobic anxiety andavoidance for 3-7 days. The invention provides a method wherein maximalmean improvements in ratings of said phobic anxiety and avoidance werenoted after approximately 2 weeks of maintenance treatment. Theinvention provides a method further comprising administering apharmaceutically effective dose of a second or additional agent, whereinsaid second or additional agent is has antianxiety properties. Theinvention provides a method wherein which further comprises anadditional therapy selected from: at least one antidepressant selectedfrom the group consisting of citalopram, escitalopram oxalate,fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, venlafaxineand duloxetine, harmaline, iproniazid, isocarboxazid, nialamide,pargyline, phenelzine, selegiline, toloxatone, tranylcypromine,brofaromine, moclobemide, amitriptyline, amoxapine, butriptyline,clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine,iprindole, lofepramine, melitracen, nortriptyline, opipramol,protriptyline, trimipramine, agomelatine, maprotiline, mianserin,nefazodone, trazodone, pharmaceutically acceptable salts, isomers, andcombinations thereof, at least one serotonin 1a partial agonist selectedfrom the group consisting of buspirone, eltoprazine, or tandospirone,pharmaceutically acceptable salts, isomers, and combinations thereof, atleast one alpha-2-delta ligand selected from the group consisting ofgabapentin, pregabalin, 3-methylgabapentin, (1 alpha,3alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,(3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoicacid, (3S,5R)-3 amino-5 methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantiadrenergic agents selected from the group consisting of clonidine,prazosin, propranolol, fuanfacine, methyldopa, guanabenz; doxazosin,prazosin, terazosin, silodosin, alfuzosin, tamsulosin,dutasteride/tamsulosin, guanadrel, mecemylamine, guanethidine,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one benzodiazepine agent selected from the group consisting ofalprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam,clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam,nimetazepam, estazolam, flunitrazepam, oxazepam (Serax), temazepam,Restoril, Normison, Planum, Tenox, Temaze, triazolam, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantipsychotic agent selected from the group consisting of haloperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine,levomepromazine, promethazine, chlorprothixene, flupenthixol,thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone,quetiapine, ziprasidone, amisulpride, paliperidone, dopamine,bifeprunox, norclozapine, aripiprazole, tetrabenazine, cannabidiol,pharmaceutically acceptable salts, isomers, and combinations thereof;other therapeutic interventions selected from the group consisting ofcounseling, psychotherapy, cognitive therapy, exposure and otherbehavioural therapies electroconvulsive therapy, hydrotherapy,hyperbaric oxygen therapy, electrotherapy and electrical stimulation,transcutaneous electrical nerve stimulation (“TENS”), deep brainstimulation, vagus nerve stimulation, and transcranial magneticstimulation, and combinations thereof.

The invention provides for the use of the compositions of the inventionfor the production of a medicament for treating the indications as setforth herein.

In accordance with a further embodiment, the present invention providesa use of the pharmaceutical compositions described herein, in an amounteffective for use in a medicament, and most preferably for use as amedicament for treating a disease or disorder in a subject.

In accordance with yet another embodiment, the present inventionprovides a use of the pharmaceutical compositions described herein, andat least one additional therapeutic agent, in an amount effective foruse in a medicament, and most preferably for use as a medicament fortreating a disease or disorder associated with disease in a subject.

The invention provides a method of treating a patient for DSM-5 SpecificPhobia, comprising: selecting a patient in need of such treatment; andorally administering to the patient a tablet comprising: (A) a corecomprising: i) a therapeutically effective amount of an active agentselected from the group consisting of ketamine, norketamine,pharmaceutically acceptable salts thereof, and combinations thereof; ii)at least one high molecular weight polyethylene oxide (PEO) that iscured, wherein said high molecular weight PEO has an approximatemolecular weight of from about 2 million to about 7 million, based uponrheological measurements, and is present in an amount of at least about30% (by weight) of the core; (B) a coating on said core,

wherein said tablet is crush resistant and has a breaking strength of atleast about 200 N; and provides a mean t_(max) of said active agent atleast about 4 hours after administration of a single tablet to apatient, wherein the tablet treats the symptoms of said DSM-5 SpecificPhobia. The invention provides a method wherein the molecular weight ofsaid high molecular weight PEO is selected from the group consisting ofat least about 2,000,000, at least about 4,000,000; at least about5,000,000; at least about 6,000,000; and at least about 7,000,000. Theinvention provides a method wherein the active agent comprises at leastabout 1% (by weight) of the core. The invention provides a methodwherein said high molecular weight PEO comprises at least about 50% (byweight) of said core. The invention provides a method wherein the dosageamount of active agent is selected from the group consisting of about 1mg, about 2 mg, about 5 mg, about 10 mg, about 30 mg, about 60 mg, about120 mg, and about 240 mg. The invention provides a method wherein thetablet is cured at a temperature of about 70° C. to about 75° C. Theinvention provides a method wherein the coating comprises: i)hydroxypropylmethylcellulose; ii) titanium dioxide; and iii)polyethylene glycol. The invention provides a method wherein said tabletprovides a ketamine C_(max) between about 12 and about 42 ng/mL. Theinvention provides a method wherein said tablet provides a ketamineAUC_(0-inf) between about 79 and about 385 ng·h/mL. The inventionprovides a method wherein said tablet provides a norketamine C_(max)between about 74 and about 315 ng/mL. The invention provides a methodwherein said tablet provides a norketamine AUC_(0-inf) between about 872and about 4079 ng·h/mL. The invention provides a method wherein the meant_(max) of said active agent is selected from the group consisting of atleast about 4 hours, at least about 6 hours, at least about 8 hours, atleast about 10 hours, at least about 11 hours, and at least about 12hours. The invention provides a method wherein the tablet is suitablefor once daily administration or twice-daily administration to apatient. The invention provides a method wherein the symptoms of saidDSM-5 Specific Phobia are alleviated within 2 hours of oraladministration of said ketamine. The invention provides a method whereinsaid method comprises oral administration of a single dose of saidketamine. The invention provides a method wherein said method comprisesoral administration of multiple doses of said ketamine.

The invention provides a method wherein a single oral administration ofsaid ketamine in doses between 30-180 mg is sufficient to alleviate theeffects of said DSM-5 Specific Phobia for 3-7 days. The inventionprovides a method wherein tablet has no or minimal dissociative sideeffects in the patient. The invention provides a method wherein thedosing frequency of the ketamine formulation ranges from once weekly,twice weekly, three times weekly, up to daily administration to apatient. The invention provides a method wherein the DSM-5 SpecificPhobia is selected from the group consisting of environmental phobia,animal phobia, situational phobia, bodily phobia, and combinationsthereof. The invention provides a method wherein the environmentalphobia is selected from the group consisting of fear of germs, deepwater, heights, other environmental phobias, and combinations thereof.The invention provides a method wherein the animal phobia is selectedfrom the group consisting of fear of dogs, spiders, snakes, other animalphobias, and combinations thereof. The invention provides a methodwherein the situational phobia is selected from the group consisting offear of flying in an aeroplane, visiting the dentist, other situationalphobias, and combinations thereof. The invention provides a methodwherein the bodily phobia is selected from the group consisting of fearof blood exposure, other bodily phobias, and combinations thereof. Theinvention provides a method wherein the symptoms of said specific phobiaare alleviated within 1-3 hours of administration of said ketamineformulations. The invention provides a method wherein said methodcomprises single dose administration of said ketamine formulations. Theinvention provides a method wherein said method comprises multiple doseadministrations of said ketamine formulations. The invention provides amethod wherein a single administration of said ketamine formulations indoses between 30-180 mg is sufficient to alleviate the effects of saidphobic anxiety and avoidance for 3-7 days. The invention provides amethod wherein maximal mean improvements in ratings of DSM-5 SpecificPhobia were noted after approximately 2 weeks of maintenance treatment.The invention provides a method further comprising administering apharmaceutically effective dose of a second or additional agent, whereinsaid second or additional agent is has antianxiety properties. Theinvention provides a method wherein said method further comprises anadditional therapy selected from: at least one antidepressant selectedfrom the group consisting of citalopram, escitalopram oxalate,fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxineand duloxetine; harmaline, iproniazid, isocarboxazid, nialamide,pargyline, phenelzine, selegiline, toloxatone, tranylcypromine,brofaromine, moclobemide; amitriptyline, amoxapine, butriptyline,clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine,iprindole, lofepramine, melitracen, nortriptyline, opipramol,protriptyline, trimipramine; agomelatine, maprotiline, mianserin,nefazodone, trazodone, pharmaceutically acceptable salts, isomers, andcombinations thereof; at least one serotonin 1a partial agonist selectedfrom the group consisting of buspirone, eltoprazine, or tandospirone,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one alpha-2-delta ligand selected from the group consisting ofgabapentin, pregabalin, 3-methylgabapentin, (1alpha,3alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,(3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoicacid, (3S,5R)-3 amino-5 methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantiadrenergic agents selected from the group consisting of clonidine,prazosin, propranolol, fuanfacine, methyldopa, guanabenz; doxazosin,prazosin, terazosin, silodosin, alfuzosin, tamsulosin,dutasertide/tamsulosin, guanadrel, mecemylamine, guanethidine,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one benzodiazepine agent selected from the group consisting ofalprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam,clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam,nimetazepam, estazolam, flunitrazepam, oxazepam (Serax), temazepam,Restoril, Normison, Planum, Tenox, Temaze, triazolam, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantipsychotic agent selected from the group consisting of haloperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine,levomepromazine, promethazine, chlorprothixene, flupenthixol,thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone,quetiapine, ziprasidone, amisulpride, paliperidone, dopamine,bifeprunox, norclozapine, aripiprazole, tetrabenazine, cannabidiol,pharmaceutically acceptable salts, isomers, and combinations thereof;other therapeutic interventions selected from the group consisting ofcounseling, psychotherapy, cognitive therapy, exposure and otherbehavioural therapies electroconvulsive therapy, hydrotherapy,hyperbaric oxygen therapy, electrotherapy and electrical stimulation,transcutaneous electrical nerve stimulation (“TENS”), deep brainstimulation, vagus nerve stimulation, and transcranial magneticstimulation, and combinations thereof.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

The invention will be described in conjunction with the followingdrawings in which like reference numerals designate like elements andwherein:

FIG. 1 is a chart showing dissolution profiles of the 60 mg sustainedrelease ketamine tablet at 3 different pHs.

FIG. 2A is a chart showing the mean dissociation scale scores, using theClinician-Administered Dissociative States Scale (CADSS) after a singledose of the sustained release tablet; FIG. 2B is a chart showing meanCADSS scores after multiple doses of the tablet, Cohorts 1-3.

FIG. 3A is a chart showing mean concentration-time profiles of ketamineand norketamine after single dose, Cohorts 1-3; FIG. 3B is a chartshowing mean concentration-time profiles of ketamine and norketamineafter multiple doses, Cohorts 1-3.

FIG. 4A is a chart showing ketamine maximum concentration (Cmax)dose-proportionality after single doses of 60 mg, 120 mg and 240 mgextended release ketamine tablets; FIG. 4B is a chart showing ketamineArea under the Concentration-Time curve (AUC) after single doses of 60mg, 120 mg and 240 mg extended release ketamine tablets; FIG. 4C is achart showing ketamine maximum concentration (Cmax) dose-proportionalityafter multiple doses of 60 mg, 120 mg and 240 mg extended releaseketamine tablets; FIG. 4D is a chart showing ketamine Area under theConcentration-Time curve (AUC) after multiple doses of 60 mg, 120 mg and240 mg extended release ketamine tablets; FIG. 4E is a chart showingnorketamine maximum concentration (Cmax) dose-proportionality aftersingle doses of 60 mg, 120 mg and 240 mg extended release norketaminetablets; FIG. 4F is a chart showing norketamine Area under theConcentration-Time curve (AUC) after single doses of 60 mg, 120 mg and240 mg extended release norketamine tablets; FIG. 4G is a chart showingnorketamine maximum concentration (Cmax) dose-proportionality aftermultiple doses of 60 mg, 120 mg and 240 mg extended release norketaminetablets; FIG. 4H is a chart showing norketamine Area under theConcentration-Time curve (AUC) after multiple doses of 60 mg, 120 mg and240 mg extended release norketamine tablets, Cohorts 1-3.

FIG. 5A is a chart showing the individual and mean CADSS scores, Cohort4 after dosing with extended release ketamine tablets. FIG. 5B is achart showing the comparison of mean CADS S scores over 3 hours afterinitial dosing with ketamine tablets (filled symbols) and subcutaneousketamine (open symbols) in the 6 Cohort 4 participants with both sets ofdata.

FIG. 6A is a chart showing the individual and mean Hamilton AnxietyScale (HAMA) scores, Cohort 4 after dosing with extended releaseketamine tablets. FIG. 6B is a chart showing the individual and meanFear Questionnaire (FQ) scores, Cohort 4 after dosing with extendedrelease ketamine tablets.

FIG. 7 is a chart showing comparison of mean HAMA scores after initialdosing with ketamine tablets (filled symbols) and subcutaneous ketamine(open symbols) in the 6 Cohort 4 participants with both sets of data.

FIG. 8 is a chart showing individual and mean Montgomery-AsbergDepression Rating Scale (MADRS) scores, Cohort 4 after dosing withextended release ketamine tablets.

FIG. 9A is a chart showing the smoothed mean depression (MADRS) scoresin 3 patients in Cohort 4, who entered a subsequent 3 month open-labelextension (OLE) phase;

FIG. 9B is a chart showing anxiety (FQ) scores in the 3 patients inCohort 4 who entered a subsequent 3 month open-label extension (OLE)phase; FIG. 9C is a chart showing anxiety (HAMA) scores in the 3patients in Cohort 4 who entered a subsequent 3 month open-labelextension (OLE) phase. All three patients reported improvements in moodratings during this time. Mean depression ratings appeared to take 6weeks for maximal improvement (FIG. 9A), whereas mean maximal anxietyscale improvement appeared to occur by week 2 (FIGS. 9B, 9C).

FIG. 10 is a chart showing individual and mean concentration-timeprofiles of ketamine and norketamine, Cohort 4. Mean dose administeredat each 12 hour interval is shown above the concentration-time plots.

FIG. 11 is a chart showing changes in individual ketamine:norketamineratios associated with 12 hourly dosing of extended release ketaminetablets, with a fitted regression line, Cohort 4.

FIG. 12 is a graph showing the effects of ketamine dose on mean FearQuestionnaire Blood Injury (FQBI) scale scores, predose to 168 hpost-dose

FIG. 13A is a graph showing changes from baseline in FQBI scores at 2hours in relation to ketamine. The baseline FQBI scores are shown inred, with error bars representing the standard deviation (n=30).

FIG. 13B is a graph showing changes from baseline in FQBI scores at 2hours in relation to norketamine concentrations at 2 hours. The baselineFQBI scores are shown in red, with error bars representing the standarddeviation (n=30).

FIG. 14 is a graph showing the effects of maintenance ketamine treatmenton mean FQBI scores over 14 weeks, predose and 1 and 2 h post-dose. TheFQBI score prior to receiving any ketamine is also shown (grey symbol).

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term “active pharmaceutical ingredient” (“API”) or“pharmaceutically active agent” is a drug or agent which can be employedfor the invention and is intended to be used in the human or animal bodyin order to heal, to alleviate, to prevent or to diagnose diseases,ailments, physical damage or pathological symptoms; allow the state, thecondition or the functions of the body or mental states to beidentified; to replace active substances produced by the human or animalbody, or body fluids; to defend against, to eliminate or to renderinnocuous pathogens, parasites or exogenous substances or to influencethe state, the condition or the functions of the body or mental states.Drugs in use can be found in reference works such as, for example, theRote Liste or the Merck Index. Examples which may be mentioned includeketamine.

An amount is “effective” as used herein, when the amount provides aneffect in the subject. As used herein, the term “effective amount” meansan amount of a compound or composition sufficient to significantlyinduce a positive benefit, including independently or in combinationsthe benefits disclosed herein, but low enough to avoid serious sideeffects, i.e., to provide a reasonable benefit to risk ratio, within thescope of sound judgment of the skilled artisan. For those skilled in theart, the effective amount, as well as dosage and frequency ofadministration, may easily be determined according to their knowledgeand standard methodology of merely routine experimentation based on thepresent disclosure.

As used herein, the terms “subject” and “patient” are usedinterchangeably. As used herein, the term “patient” refers to an animal,preferably a mammal such as a non-primate (e.g., cows, pigs, horses,cats, dogs, rats etc.) and a primate (e.g., monkey and human), and mostpreferably a human. In some embodiments, the subject is a non-humananimal such as a farm animal (e.g., a horse, pig, or cow) or a pet(e.g., a dog or cat). In a specific embodiment, the subject is anelderly human. In another embodiment, the subject is a human adult. Inanother embodiment, the subject is a human child. In yet anotherembodiment, the subject is a human infant.

As used herein, the phrase “pharmaceutically acceptable” means approvedby a regulatory agency of the federal or a state government, or listedin the U.S. Pharmacopeia, European Pharmacopeia, or other generallyrecognized pharmacopeia for use in animals, and more particularly, inhumans.

As used herein, the term “excipient” means the substances used toformulate active pharmaceutical ingredients (API) into pharmaceuticalformulations; in a preferred embodiment, an excipient does not lower orinterfere with the primary therapeutic effect of the API. Preferably, anexcipient is therapeutically inert. The term “excipient” encompassescarriers, diluents, vehicles, solubilizers, stabilizers, bulking agents,acidic or basic pH-adjusting agents and binders. Excipients can also bethose substances present in a pharmaceutical formulation as an indirector unintended result of the manufacturing process. Preferably,excipients are approved for or considered to be safe for human andanimal administration, i.e., GRAS substances (generally regarded assafe). GRAS substances are, for example, listed by the U.S. Food andDrug administration in the Code of Federal Regulations (CFR) at 21 CFR182 and 21 CFR 184, incorporated herein by reference.

As used herein, the terms “prevent,” “preventing” and “prevention” inthe context of the administration of a therapy to a subject refer to theprevention or inhibition of the recurrence, onset, and/or development ofa disease or condition, or a combination of therapies (e.g., acombination of prophylactic or therapeutic agents).

As used herein, the terms “therapies” and “therapy” can refer to anymethod(s), composition(s), and/or agent(s) that can be used in theprevention, treatment and/or management of a disease or condition, orone or more symptoms thereof.

As used herein, the terms “treat,” “treatment,” and “treating” in thecontext of the administration of a therapy to a subject refer to thereduction or inhibition of the progression and/or duration of a diseaseor condition, the reduction or amelioration of the severity of a diseaseor condition, and/or the amelioration of one or more symptoms thereofresulting from the administration of one or more therapies.

As used herein, the term “about” when used in conjunction with a statednumerical value or range has the meaning reasonably ascribed to it by aperson skilled in the art, i.e. denoting somewhat more or somewhat lessthan the stated value or range.

Administration: The application or delivery of a drug to a patient inneed of the drug. This term is intended to include any means ofadministration which accomplishes the application or delivery of thedrug (i. e., topical, oral, aerosol, suppository, parenteral, e. g.,intravenous, intramuscular, subcutaneous injection, e. g., into thetissue, intraperitoneally and the like). The term is also intended toinclude any means necessary to accomplish such administration. The termis further intended to include the in vivo production of a drug oraggregation of a drug moderated by another substance such as an enzymeor enzyme gene to affect production of a drug or its precursors.

Depression

Depression is characterized by depressed mood, and markedly diminishedinterest or pleasure in activities. Other symptoms include significantweight loss or weight gain, decrease or increase in appetite, insomniaor hypersomnia, psychomotor agitation or retardation, fatigue or loss ofenergy, feelings of worthlessness or excessive or inappropriate guilt,diminished ability to think or concentrate or indecisiveness, recurrentthoughts of death, suicidal ideation or suicidal attempts. A variety ofsomatic symptoms may also be present. Though depressive feelings arecommon, especially after experiencing setbacks in life, depressivedisorder is diagnosed only when the symptoms reach a threshold and lastat least two weeks. Depression can vary in severity from mild to verysevere. It is most often episodic but can be recurrent or chronic. Somepeople have only a single episode, with a full return to premorbidfunction. However, more than 50 percent of those who initially suffer asingle major depressive episode eventually develop another.

Treatment resistant-depression includes unipolar depression that doesnot respond satisfactorily to one or more treatments that are optimallydelivered. If the depression has not benefited from at least twoadequate trials of medications from different classes in the currentepisode, clinically significant treatment resistance is present.

Any chronic, treatment-resistant depression may be treated by themethods described herein. Such depression may include but is not limitedto any of: major depressive disorder, single episode, recurrent majordepressive disorder-unipolar depression, seasonal affectivedisorder-winter depression, bipolar mood disorder-bipolar depression,mood disorder due to a general medical condition—with majordepressive-like episode, or mood disorder due to a general medicalcondition—with depressive features, wherein those disorders areresistant to treatment in a given patient. Thus, any patient thatpresents one of those disorders and who has not responded to an adequatetrial of one antidepressant in the current episode and has recurrent orchronic depressive symptoms for greater than 2 years can be treated bythe methods of the invention. Manic Depressive illnesses are alsodescribed in Goodwin, et al. 2007.

Anxiety is a mood disorder characterized by nervousness, fear,apprehension, and worrying. Patients with anxiety disorders may reportsymptoms such as excessive worry, panic attacks, or avoidance ofspecific situations (e.g. social interactions, supermarkets). Treatmentresistant anxiety (TRA; anxiety that has not resolved or improveddespite adequate medication and psychotherapy) is relatively common,with approximately 30% of patients showing no response to treatment, anda further 30-40% of patients having a partial response (Brown 1996). Nodrug treatments are approved at present for TRA.

Autoinduction is the ability of a drug to induce enzymes that enhanceits own metabolism, which may result in tolerance.

Phobias

Phobias are irrational fears that lead people to altogether avoidspecific objects or situations that trigger intense anxiety. Phobiasoccur in several forms, for example, agoraphobia is the fear of being inany situation that might trigger a panic attack and from which escapemight be difficult. Social Phobia or Social Anxiety Disorder is the fearof social situations and the interaction with other people, which canautomatically bring on feelings of self-consciousness, judgment,evaluation, and criticism. It is the fear and anxiety of being judgedand evaluated negatively by other people, leading to feelings ofinadequacy, embarrassment, humiliation, and depression. Many of thephysical symptoms that accompany panic attacks—such as sweating, racingheart, and trembling—also occur with phobias.

Phobias include specific phobias and complex phobias. Specific phobia isan anxiety disorder of which the essential feature is a persistent fearof a circumscribed stimulus, which may be an object or situation, otherthan fear of having a panic attack or of humiliation or embarrassment insocial situations (which falls under social phobia). Examples includephobias of flying, heights, animals, injections, and blood. Simplephobias may be referred to as “specific” phobias. Exposure to the phobicstimulus will almost invariably lead to an immediate anxiety response.Social phobia is one type of complex phobia, and is characterized by thepersistent fear of social or performance situations in whichembarrassment may occur.

In DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders (5thed.; DSM-5; American Psychiatric Association, 2013), phobic disordersare anxiety states associated with intense fear or anxiety of situationsor objects, and avoidance of those situations/objects. Phobic disordershave been subdivided into complex phobias (e.g. social anxiety disorderand agoraphobia), and simple or specific phobias (e.g. fear of heights,spiders, flying, blood). Specific phobias are common, with a 12 monthprevalence of 7.3% and lifetime prevalence of 10.8% (NZ Mental HealthSurvey). In contrast to complex phobias, there are few treatment optionsfor specific phobias. Psychological therapies such as systematicdesensitization and cognitive behaviour therapy may be effective. Thereare few medication trials in patients with specific phobias, and nodrugs have regulatory approval for this indication.

A recent analysis of Fear Questionnaire (Marks and Mathews) subscaledata in 24 patients with treatment refractory anxiety showed that singlesubcutaneous doses of ketamine 0.25-1 mg/kg reduced ratings of thespecific phobia Blood Phobia subscale in a dose-dependent manner (Glueunsubmitted manuscript). There was a positive dose-response relationshipidentified between FQBI scores at 2 hours and concentrations of ketamine(FIG. 2A) and norketamine at 2 hours (FIG. 2B); specifically lowerscores were associated with higher drug concentrations. Compared withketamine, there was a greater R² value for an exponential decline curvefor the 2 hour norketamine concentrations and FQBI scores, which couldsupport a greater role for norketamine in this clinical effect.

These improvements were maintained during a 3-month maintenancetreatment phase. Ketamine appears to have broad anti-anxiety andantidepressant effects, and we have hypothesized that it may be workingvia an effect on neuroticism, a personality trait associated withinternalizing disorders including specific phobia (Glue 2018).

The present invention may affect the somatic (e.g., peripheral andvisceral) symptoms as well as the psychic (cognitive and emotional)symptoms of phobic disorders.

The invention provides a method of treating and/or preventing DSM-5Specific Phobia wherein the DSM-5 Specific Phobia is selected from thegroup consisting of, for example, environmental phobia, animal phobia,situational phobia, bodily phobia, and combinations thereof. In certainembodiments, the environmental phobia is selected from the groupconsisting of, for example, fear of germs, deep water, heights, otherenvironmental phobias, and combinations thereof. In certain embodiments,the animal phobia is selected from the group consisting of, for example,fear of dogs, spiders, snakes, other animal phobias, and combinationsthereof. In certain embodiments, the situational phobia is selected fromthe group consisting of, for example, fear of flying in an aeroplane,visiting the dentist, other situational phobias, and combinationsthereof. In certain embodiments, the bodily phobia is selected from thegroup consisting of, for example, fear of blood exposure, other bodilyphobias, and combinations thereof.

The data presented in this application were based on subcutaneousdosing. However published studies have identified that theantidepressant response to ketamine is independent of route ofadministration—that is, clinically relevant improvements in mood areseen after intravenous, subcutaneous and intramuscular dosing (Loo2016), oral dosing with liquid formulations (Schoevers 2016) andsustained release oral formulations such as R-107 (Douglas patent appl),and intranasal dosing (Daly 2018).

Given ketamine's broad antidepressant and anxiolytic effects, theeffects of ketamine on anxiety associated with specific phobia will beevident via other methods of dosing, including oral dosing, andincluding extended and/or controlled release oral dosing and/ormaintenance therapy dosing regimens.

Active Agent

The pharmaceutical composition of the the invention may comprise anactive agent, selected from the group consisting of, for example,ketamine, norketamine, pharmaceutically acceptable salts thereof, andcombinations thereof. “Ketamine” as used herein is understood tocomprise the compound of formula (I)

having the IUPAC name2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Accordingly,ketamine comprises the R and S enantiomers as well as pharmaceuticallyacceptable salts or solvates thereof. In one embodiment, ketamine is(R)-ketamine or pharmaceutically acceptable salts or solvates thereof.In another embodiment, ketamine is (S)-ketamine or pharmaceuticallyacceptable salts or solvates thereof. In a further embodiment, ketamineis a racemate of (S)-ketamine and (R)-ketamine or pharmaceuticallyacceptable salts or solvates thereof, or any mixture of (S)-ketamine and(R)-ketamine or pharmaceutically acceptable salts or solvates thereof.Ketamine can preferably comprise the pharmaceutically acceptable acidaddition salts thereof. The acids which are used to prepare thepharmaceutically acceptable acid addition salts are preferably thosewhich form non-toxic acid addition salts, i.e. salts containingpharmacologically acceptable anions, such as chloride, bromide, iodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, (D,L)- and L-tartrate, (D,L)- and L-malate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate andbenzoate. A preferred salt is the hydrochloride of ketamine.

Ketamine as used herein can also comprise its metabolites. Themetabolite is norketamine or dehydronorketamine, preferably norketamine.Norketamine has the IUPAC name2-amino-2-(2-chlorophenyl)cyclohexan-1-one of formula (II)

and is obtained from ketamine through N-demethylation. Norketamine canbe provided as (R)-norketamine or pharmaceutically acceptable salts orsolvates thereof, or (S)-norketamine or pharmaceutically acceptablesalts or solvates thereof, racemate of (S)-norketamine and(R)-norketamine or pharmaceutically acceptable salts or solvatesthereof, or any mixture of (S)-norketamine and (R)-norketamine orpharmaceutically acceptable salts or solvates thereof.

In exemplary embodiments, formulations of the invention may compriseactive agent at a concentration of about 1%, about 2%, about 3%, about4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%.In exemplary embodiments, formulations of the invention may compriseactive agent at a concentration of about 1 to 20%, of about 5% to 25%,about 10% to about 20%, or about 15% to about 18%.

Combination Therapy

Methods and compositions of treating and/or preventing a condition in asubject are provided according to embodiments of the present inventionwhich include administering, in combination, a compound of the inventionas set forth herein and at least one additional therapy, such as atherapeutic agent selected from the group consisting of at least oneanti-anxiety drug, at least one anti-depressant drug, at least oneneuroleptic medication, at least one mood stabilizer drug, at least oneantipsychotic drug, at least one hypnotic, and combinations thereof. Inexemplary embodiments, the active agent is administered in combinationwith or concurrently with another therapeutic intervention to enhancethe efficacy thereof. Examples of other therapeutic interventionsinclude, but are not limited to, counseling, psychotherapy, cognitivetherapy or the like, electroconvulsive therapy, hydrotherapy, hyperbaricoxygen therapy, electrotherapy and electrical stimulation,transcutaneous electrical nerve stimulation or “TENS” (e.g., for thetreatment of pain such as neuropathic pain), deep brain stimulation(e.g., for the treatment of pain such as neuropathic pain, Parkinson'sdisease, tremor, dystonia, etc.), vagus nerve stimulation and/ortranscranial magnetic stimulation, etc.

In exemplary embodiments, at least one anti-anxiety drug is alprazolam,bromazepam, diazepam, lorazepam, clonazepam, temazepam, oxazepam,flunitrazepam, triazolam, chlordiazepoxide, flurazepam, estazolam,nitrazepam, and pharmaceutically acceptable salts, isomers, and mixturesthereof. Further examples of anxiolytic drugs include, but are notlimited to, benzodiazepines (e.g., alprazolam, bromazepam (LEXOTAN),chlordiazepoxide (LIBRIUM), clobazam, clonazepam, clorazepate, diazepam,midazolam, lorazepam, nitrazepam, nimetazepam, estazolam, flunitrazepam,oxazepam (Serax), temazepam (RESTORIL, NORMISON, PLANUM, TENOX, andTEMAZE), triazolam, serotonin 1A agonists (e.g., buspirone (BUSPAR)),barbiturates (e.g., amobarbital (amytal sodium), pentobarbital(NEMBUTAL), secobarbital (SECONAL), phenobarbital, methohexital,thiopental, methylphenobarbital, metharbital, barbexaclone),hydroxyzine, cannabidiol, and herbal treatments. (e.g., valerian, kava(Kava Kava), chamomile, Kratom, Blue Lotus extracts, Sceletium tortuosum(kanna) and Bacopa monniera).

In exemplary embodiments, at least one anti-depressant drug iscitalopram, escitalopram oxalate, fluoxetine, fluvoxamine, paroxetine,sertraline, dapoxetine; venlafaxine and duloxetine; harmaline,iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, selegiline,toloxatone, tranylcypromine, brofaromine, moclobemide; amitriptyline,amoxapine, butriptyline, clomipramine, desipramine, dibenzepin,dothiepin, doxepin, imipramine, iprindole, lofepramine, melitracen,nortriptyline, opipramol, protriptyline, trimipramine; maprotiline,mianserin, nefazodone, trazodone, and pharmaceutically acceptable salts,isomers, and combinations thereof. Anti-depressant medications includesynthesized chemical compounds as well as naturally occurring or herbalremedies such as St. John's Wort.

Herbal antidepressants may include, for example, St John's Wort; kavakava; echinacea; saw palmetto; holy basil; valerian; milk thistle;Siberian ginseng; Korean ginseng; ashwagandha root; nettle; Ginkgobiloba; gotu kola; ginkgo/gotu kola supreme; astragalus; goldenseal;dong quai; ginseng; St. John's wort supreme; echinacea; bilberry, greentea; hawthorne; ginger, gingko, turmeric; boswellia serata; blackcohosh; cats claw; catnip; chamomile; dandelion; chaste tree berry;black elderberry; feverfew; garlic; horse chestnut; licorice; red cloverblossom and leaf Rhodiola rusa; Coleus forskohlii; Passion Flower;eyebright; yohimbe; blueberry plant; black pepper plant; Hydrocotyleasiatica; astragalus; valerian poppy root and grape seed;

vervain; echinacea ang root; Skull Cap; serenity elixir; andcombinations thereof. Examples of antidepressants include, but are notlimited to, selective serotonin reuptake inhibitors (SSRIs) (e.g.,fluoxetine (PROZAC), paroxetine (PAXIL, SEROXAT), escitalopram (LEXAPRO,ESIPRAM), citalopram (CELEXA), and sertraline (ZOLOFT)),serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine(EFFEXOR), and duloxetine (CYMBALTA)), noradrenergic and specificserotonergic antidepressants (NASSAs) (e.g., mirtazapine (AVANZA,ZISPIN, REMERON)), norepinephrine (noradrenaline) reuptake inhibitors(NRIs) (e.g., reboxetine (EDRONAX)), norepinephrine-dopamine reuptakeinhibitors (e.g., bupropion (WELLBUTRIN, ZYBAN)), tricyclicantidepressants (TCAs) (e.g., amitriptyline and desipramine), monoamineoxidase inhibitor (MAOIs) (e.g., phenelzine (NARDIL), moclobemide(MANERIX), selegiline), and augmentor drugs (e.g., tryptophan (TRYPTAN)and buspirone (BUSPAR)).

In exemplary embodiments, at least one neuroleptic drug is haloperidol(HALDOL), droperidol, benperidol, triperidol, melperone, lenperone,azaperone, domperidone, risperidone, chlorpromazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, trifluoperazine,mesoridazine, periciazine, promazine, triflupromazine, levomepromazine,promethazine, pimozide, cyamemazine, chlorprothixene, clopenthixol,flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine,risperidone, quetiapine, ziprasidone, amisulpride, asenapine,paliperidone, iloperidone, zotepine, sertindole, lurasidone,aripiprazole, and pharmaceutically acceptable salts, isomers, andcombinations thereof,

In exemplary embodiments, at least one mood stabilizer drugs includes,but is not limited to, Lithium carbonate, lithium orotate, lithium salt,Valproic acid (DEPAKENE), divalproex sodium (DEPAKOTE), sodium valproate(DEPACON), Lamotrigine (LAMICTAL), Carbamazepine (TEGRETOL), Gabapentin(NEURONTIN), Oxcarbazepine (TRILEPTAL), and Topiramate (TOPAMAX), andcombinations thereof.

Examples of antipsychotic drugs include, but are not limited to,butyrophenones (e.g., haloperidol), phenothiazines (e.g., chlorpromazine(THORAZINE), fluphenazine (PROLIXIN), perphenazine (TRILAFON),prochlorperazine (COMPAZINE), thioridazine (MELLARIL), trifluoperazine(STELAZINE), mesoridazine (SERENTIL), promazine, triflupromazine(VESPRIN), levomepromazine (NOZINAN), promethazine (PHENERGAN)),thioxanthenes (e.g., chlorprothixene (TRUXAL), flupenthixol (DEPIXOL andFLUANXOL), thiothixene (NAVANE), zuclopenthixol (CLOPIXOL & ACUPHASE)),clozapine, olanzapine, risperidone (RISPERDAL), quetiapine (SEROQUEL),ziprasidone (GEODON), amisulpride (SOLIAN), paliperidone (INVEGA),dopamine, bifeprunox, norclozapine (ACP-104), Aripiprazole (ABILIFY),tetrabenazine (XENAZINE), and cannabidiol and pharmaceuticallyacceptable salts, isomers, and combinations thereof.

Examples of hypnotics include, but are not limited to, barbiturates,opioids, benzodiazepines (e.g., alprazolam, bromazepam (Lexotan),chlordiazepoxide (Librium), clobazam, clonazepam, clorazepate, diazepam,midazolam, lorazepam, nitrazepam, nimetazepam, estazolam, flunitrazepam,oxazepam (SERAX), temazepam (RESTORIL, NORMISON, PLANUM, TENOX, andTEMAZE), triazolam), nonbenzodiazepines (e.g., ZOLPIDEM, ZALEPLON,ZOPICLONE, ESZOPICLONE), antihistamines (e.g., diphenhydramine,doxylamine, hydroxyzine, promethazine), gamma-hydroxybutyric acid(Xyrem), Glutethimide, Chloral hydrate, Ethchlorvynol, Levomepromazine,Chlormethiazole, Melatonin, and Alcohol. Examples of sedatives include,but are not limited to, barbituates (e.g., amobarbital (Amytal),pentobarbital (Nembutal), secobarbital (Seconal), phenobarbital,methohexital, thiopental, methylphenobarbital, metharbital,barbexaclone), benzodiazepines (e.g., alprazolam, bromazepam (LEXOTAN),chlordiazepoxide (LIBRIUM), clobazam, clonazepam, clorazepate, diazepam,midazolam, lorazepam, nitrazepam, nimetazepam, estazolam, flunitrazepam,oxazepam (SERAX), temazepam (RESTORIL, NORMISON, PLANUM, TENOX, andTEMAZE), triazolam), and pharmaceutically acceptable salts, isomers, andcombinations thereof. Examples further include Herbal sedatives (e.g.,ashwagandha, catnip, kava (Piper methysticum), mandrake, marijuana,valerian), solvent sedatives (e.g., chloral hydrate (NOCTEC), diethylether (Ether), ethyl alcohol (alcoholic beverage), methyl trichloride(chloroform)), nonbenzodiazepine sedatives (e.g., eszopiclone (LUNESTA),zaleplon (SONATA), zolpidem (AMBIEN), zopiclone (IMOVANE, ZIMOVANE)),clomethiazole, gamma-hydroxybutyrate (GHB), thalidomide, ethchlorvynol(PLACIDYL), glutethimide (DORIDEN), ketamine (KETALAR, KETASET),methaqualone (SOPOR, QUAALUDE), methyprylon (NOLUDAR), and ramelteon(ROZEREM).

Examples of alpha-2-delta ligand include gabapentin, pregabalin,3-methylgabapentin, (1alpha,3alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,(3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoicacid, (3S,5R)-3 amino-5 methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, and combinations thereof.

Examples of serotonin 1a partial agonist include buspirone, gepirone,eltoprazine, or tandospirone, pharmaceutically acceptable salts,isomers, and combinations thereof.

Examples of antiadrenergic agents include clonidine, prazosin,propranolol, fuanfacine, methyldopa, guanabenz; doxazosin, prazosin,terazosin, silodosin, alfuzosin, tamsulosin, dutasertide/tamsulosin,guanadrel, mecemylamine, guanethidine, pharmaceutically acceptablesalts, isomers, and combinations thereof.

Examples of benzodiazepine agents include alprazolam, bromazepam(LEXOTAN), chlordiazepoxide (LIBRIUM), clobazam, clonazepam,clorazepate, diazepam, midazolam, lorazepam, nitrazepam, nimetazepam,estazolam, flunitrazepam, oxazepam (SERAX), temazepam (RESTORIL,NORMISON, PLANUM, TENOX, and TEMAZE), triazolam, pharmaceuticallyacceptable salts, isomers, and combinations thereof.

The agents are administered in therapeutically effective amounts. Incertain embodiments the agents are administered in the same dosage form.In certain embodiments the therapeutic agents are administeredseparately.

Pharmacokinetics

The formulation of the invention provides extended release of ketamineof, for example, over 4 hours, over 5 hours, over 6 hours, over 7 hours,over 8 hours, over 9 hours, over 10 hours, or more. Eliminationhalf-life estimates for ketamine and norketamine for the formulation asset forth herein are much longer that previously reported for immediaterelease tablet formulations (e.g. 8 hr vs<2 hr; Yanagihara 2002)

There is evidence that the formulations of the invention provide forautoinduction (FIG. 10). This appears to have stabilized after 3-4 daysof repeat dosing. There is no prior human data on this.

There is evidence for the formulations of the invention that over 90% ofthe absorbed drug is present as norketamine rather than ketamine. In thepatient cohort (cohort 4) there were improvements in depression andanxiety despite the major measurable drug present being norketamine.There has been much discussion in the scientific literature aboutwhether ketamine or a metabolite are important in producing improvementsin mood after dosing with ketamine. Zanos 2016 and Zarate 2017 highlightketamine's metabolite, 6-hydroxy norketamine as important. The inventorshave surprisingly found that norketamine itself is important in thetablet's therapeutic effects. This is in contrast to a previous reportwhich presented data as combined ketamine and norketamine, rather thanseparately, and did not report on the importance of norketamine to thetherapeutic effect. (See WO 2015/031410).

The oral formulation as set forth herein has no dissociative sideeffects after 60-120 mg doses, and minimal dissociative side effects at240 mg (FIGS. 2A and 2B). This contrasts markedly with injected ketamineby any route of administration (e.g. Loo 2016), where there are markeddissociative symptoms for up to 60 minutes after dosing.

There is evidence that the formulations of the invention are efficaciousin improving both depressed and anxious mood, with improved tolerabilitycompared with injected ketamine. For example, a leading research grouphas highlighted a finding that having a dissociative experience iscritical to mood improvement in TRD. “Among the examined mediators ofketamine's antidepressant response, only dissociative side effectspredicted a more robust and sustained antidepressant”(ncbi.nlm.nih.gov/pubmed/24679390). The inventors have found thatimprovement in depression scores occurs with no or minimal dissociation(see FIGS. 8 and 5A). This observation of improvement in depressionscores in the absence of dissociation is novel and nonobvious.

The onset of improvement of anxiety symptoms in study 603 cohort 4 wasmore gradual (48 h) compared with 1-2 h for injected ketamine (FIG. 7),however the same overall magnitude of effect was observed as withinjected drug in earlier treatment.

Furthermore, a safe and effective dose and dosing schedule have beenidentified in an open-label extension study for patients who completedthe 603 study. Three of 4 patients with mixed anxiety/depressivedisorders remained in remission on doses of 120 mg orally once or twiceweekly.

Matrix Formulations

In certain embodiments, the present invention is directed to a processof preparing a solid oral extended release pharmaceutical dosage form,comprising at least the steps of:

(a) combining:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight selected from the        group consisting of at least about 1,000,000; at least about        2,000,000; at least about 3,000,000; at least about 4,000,000;        at least about 5,000,000; at least about 6,000,000; at least        about 6,000,000; at least about 7,000,000; and at least about        8,000,000; and    -   (2) at least one active agent, to form a composition;

(b) shaping the composition to form an extended release matrixformulation; and

(c) curing said extended release matrix formulation comprising at leasta curing step of subjecting the extended release matrix formulation to atemperature which is at least the softening temperature of saidpolyethylene oxide for a time period selected from the group consistingof at least about 1 minute, at least about 2 minutes, at least about 3minutes, at least about 4 minutes, at least about 5 minutes, at leastabout 6 minutes, at least about 7 minutes, at least about 8 minutes, atleast about 9 minutes, and at least about 10 minutes. Preferably, thecuring is conducted at atmospheric pressure. In a preferred embodimentthe dosage form is coated.

In certain embodiments the composition is shaped in step b) to form anextended release matrix formulation in the form of tablet. For shapingthe extended release matrix formulation in the form of tablet a directcompression process can be used. Direct compression is an efficient andsimple process for shaping tablets by avoiding process steps like wetgranulation. However, any other process for manufacturing tablets asknown in the art may be used, such as wet granulation and subsequentcompression of the granules to form tablets.

In one embodiment, the curing of the extended release matrix formulationin step c) comprises at least a curing step wherein the high molecularweight polyethylene oxide in the extended release matrix formulation atleast partially melts. For example, at least about 20% or at least about30% of the high molecular weight polyethylene oxide in the extendedrelease matrix formulation melts. Preferably, at least about 40% or atleast about 50%, more preferably at least about 60%, at least about 75%or at least about 90% of the high molecular weight polyethylene oxide inthe extended release matrix formulation melts. In a preferredembodiment, about 100% of the high molecular weight polyethylene oxidemelts.

In other embodiments, the curing of the extended release matrixformulation in step c) comprises at least a curing step wherein theextended release matrix formulation is subjected to an elevatedtemperature for a certain period of time. In such embodiments, thetemperature employed in step c), i.e. the curing temperature, is atleast as high as the softening temperature of the high molecular weightpolyethylene oxide. Without wanting to be bound to any theory it isbelieved that the curing at a temperature that is at least as high asthe softening temperature of the high molecular weight polyethyleneoxide causes the polyethylene oxide particles to at least adhere to eachother or even to fuse. According to some embodiments the curingtemperature is at least about 60° C. or at least about 62° C., or rangesfrom about 62° C., to about 90° C., or from about 62° C. to about 85° C.or from about 62° C. to about 80° C. or from about 65° C. to about 90°C. or from about 65° C. to about 85° C. or from about 65° C. to about80° C. The curing temperature preferably ranges from about 68° C. toabout 90° C. or from about 68° C. to about 85° C. or from about 68° C.to about 80° C., more preferably from about 70° C. to about 90° C. orfrom about 70° C. to about 85° C. or from about 70° C. to about 80° C.,most preferably from about 75° C. to about 90° C. or from about 75° C.to about 85° C. or from about 72° C. to about 80° C., or from about 70°C. to about 75° C. The curing temperature may be at least about 60° C.or at least about 62° C., but less than about 90° C. or less than about80° C. Preferably, it is in the range of from about 62° C. to about 75°C., in particular from about 68° C. to about 75° C. Preferably, thecuring temperature is at least as high as the lower limit of thesoftening temperature range of the high molecular weight polyethyleneoxide or at least about 62° C. or at least about 68° C. More preferably,the curing temperature is within the softening temperature range of thehigh molecular weight polyethylene oxide or at least about 70° C. Evenmore preferably, the curing temperature is at least as high as the upperlimit of the softening temperature range of the high molecular weightpolyethylene oxide or at least about 72° C. In an alternativeembodiment, the curing temperature is higher than the upper limit of thesoftening temperature range of the high molecular weight polyethyleneoxide, for example the curing temperature is at least about 75° C. or atleast about 80° C.

The curing time may vary from about 1 minute to about 24 hours or fromabout 5 minutes to about 20 hours or from about 10 minutes to about 15hours or from about 15 minutes to about 10 hours or from about 30minutes to about 5 hours depending on the specific composition and onthe formulation and the curing temperature. The parameter of thecomposition, the curing time and the curing temperature are chosen toachieve the tamper resistance as described herein. According to certainembodiments the curing time varies from about 15 minutes to about 30minutes.

In certain embodiments of the present invention, the sustained releaseformulation may be achieved via a matrix optionally having a controlledrelease coating as set forth herein. The present invention may alsoutilize a sustained release matrix that affords in-vitro dissolutionrates of the API within desired ranges and releases the API in apH-dependent or pH-independent manner.

A non-limiting list of suitable sustained-release materials which may beincluded in a sustained-release matrix according to the inventionincludes hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil and hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic sustained-release material which is capable of impartingsustained-release of the API may be used in accordance with the presentinvention. Preferred sustained-release polymers include alkylcellulosessuch as ethylcellulose, acrylic and methacrylic acid polymers andcopolymers; and cellulose ethers, especially hydroxyalkylcelluloses(especially hydroxypropylmethylcellulose) and carboxyalkylcelluloses.Preferred acrylic and methacrylic acid polymers and copolymers includemethyl methacrylate, methyl methacrylate copolymers, ethoxyethylmethacrylates, ethyl acrylate, trimethyl ammonioethyl methacrylate,cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid), poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methylmethacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. Certain preferred embodiments utilizemixtures of any of the foregoing sustained-release materials in thematrix of the invention. The matrix also may include a binder.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids and glidants that are conventionalin the pharmaceutical art.

A sustained-release matrix can be prepared by, e.g., melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic binder material, e.g., awax, and incorporating a powdered drug therein. To obtain a sustainedrelease dosage form, it may be necessary to incorporate a hydrophobicsustained-release material, e.g., ethylcellulose or a water-insolubleacrylic polymer, into the molten wax hydrophobic binder material.

The additional hydrophobic binder material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve sustained release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theAPI with a sustained release material and preferably a binder materialto obtain a homogeneous mixture. The homogeneous mixture is then heatedto a temperature sufficient to at least soften the mixture sufficientlyto extrude the same. The resulting homogeneous mixture is then extruded,e.g., using a twin-screw extruder, to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The matrix multiparticulates are then divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the active agent or pharmaceuticallyacceptable salt thereof for a time period of at least about 24 hours.

An optional process for preparing the melt extruded formulations of thepresent invention includes directly metering into an extruder ahydrophobic sustained release material, the API, and an optional bindermaterial; heating the homogenous mixture; extruding the homogenousmixture to thereby form strands; cooling the strands containing thehomogeneous mixture; cutting the strands into matrix multiparticulateshaving a size from about 0.1 mm to about 12 mm; and dividing saidparticles into unit doses. In this aspect of the invention, a relativelycontinuous manufacturing procedure is realized.

Plasticizers, such as those described above, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, lubricants and thelike may be included in the sustained release matrices of the presentinvention as desired. The amounts included will depend upon the desiredcharacteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc.

A melt extruded matrix multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded matrix multiparticulate(s)” and “melt-extruded matrixmultiparticulate system(s)” and “melt-extruded matrix particles” shallrefer to a plurality of units, preferably within a range of similar sizeand/or shape and containing one or more active agents and one or moreexcipients, preferably including a hydrophobic sustained releasematerial as described herein. Preferably the melt-extruded matrixmultiparticulates will be of a range of from about 0.1 to about 12 mm inlength and have a diameter of from about 0.1 to about 5 mm. In addition,it is to be understood that the melt-extruded matrix multiparticulatescan be any geometrical shape within this size range. In certainembodiments, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded matrix multiparticulates within acapsule. For example, a plurality of the melt-extruded matrixmultiparticulates may be placed in a gelatin capsule in an amountsufficient to provide an effective sustained release dose when ingestedand contacted by gastrointestinal fluid.

In another embodiment, a suitable amount of the multiparticulateextrudate is compressed into an oral tablet using conventional tabletingequipment using standard techniques. Techniques and compositions formaking tablets (compressed and molded), capsules (hard and soft gelatin)and pills are described in Remington's Pharmaceutical Sciences, (ArthurOsol, editor), 1553-1593 (1980).

In addition to the above ingredients, the spheroids, granules, or matrixmultiparticulates may also contain suitable quantities of othermaterials, e.g., diluents, lubricants, binders, granulating aids, andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the formulation if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In one embodiment, at least one active agent in solubility-improved formis incorporated into an erodible or non-erodible polymeric matrixcontrolled release formulation. By an erodible matrix is meantaqueous-erodible or water-swellable or aqueous-soluble in the sense ofbeing either erodible or swellable or dissolvable in pure water orrequiring the presence of an acid or base to ionize the polymeric matrixsufficiently to cause erosion or dissolution. When contacted with theaqueous environment of use, the erodible polymeric matrix imbibes waterand forms an aqueous-swollen gel or “matrix” that entraps thesolubility-improved form of the active agent.

The aqueous-swollen matrix gradually erodes, swells, disintegrates ordissolves in the environment of use, thereby controlling the release ofthe active agent to the environment of use. The erodible polymericmatrix into which the active agent is incorporated may generally bedescribed as a set of excipients that are mixed with thesolubility-improved form following its formation that, when contactedwith the aqueous environment of use imbibes water and forms awater-swollen gel or “matrix” that entraps the drug form. Drug releasemay occur by a variety of mechanisms: the matrix may disintegrate ordissolve from around particles or granules of the drug insolubility-improved form; or the drug may dissolve in the imbibedaqueous solution and diffuse from the tablet, beads or granules of theformulation. A key ingredient of this water-swollen matrix is thewater-swellable, erodible, or soluble polymer, which may generally bedescribed as an osmopolymer, hydrogel or water-swellable polymer. Suchpolymers may be linear, branched, or crosslinked. They may behomopolymers or copolymers. Although they may be synthetic polymersderived from vinyl, acrylate, methacrylate, urethane, ester and oxidemonomers, they are most preferably derivatives of naturally occurringpolymers such as polysaccharides or proteins.

Such materials include naturally occurring polysaccharides such aschitin, chitosan, dextran and pullulan; gum agar, gum arabic, gumkaraya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guargum, xanthan gum and scleroglucan; starches such as dextrin andmaltodextrin; hydrophilic colloids such as pectin; phosphatides such aslecithin; alginates such as ammonium alginate, sodium, potassium orcalcium alginate, propylene glycol alginate; gelatin; collagen; andcellulosics. By “cellulosics” is meant a cellulose polymer that has beenmodified by reaction of at least a portion of the hydroxyl groups on thesaccharide repeat units with a compound to form an ester-linked or anether-linked substituent. For example, the cellulosic ethyl cellulosehas an ether linked ethyl substituent attached to the saccharide repeatunit, while the cellulosic cellulose acetate has an ester linked acetatesubstituent.

A preferred class of cellulosics for the erodible matrix comprisesaqueous-soluble and aqueous-erodible cellulosics such as ethyl cellulose(EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). Aparticularly preferred class of such cellulosics comprises variousgrades of low viscosity (MW less than or equal to 50,000 daltons) andhigh viscosity (MW greater than 50,000 daltons) HPMC. Commerciallyavailable low viscosity HPMC polymers include the Dow METHOCEL seriesES, E15LV, E50LV and K100LY, while high viscosity HPMC polymers includeE4MCR, E10MCR, K4M, K15M and K100M; especially preferred in this groupare the METHOCEL K series. Other commercially available types of HPMCinclude the Shin Etsu METOLOSE 90SH series.

Although the primary role of the erodible matrix material is to controlthe rate of release of the active agent in solubility-improved form tothe environment of use, the inventors have found that the choice ofmatrix material can have a large effect on the maximum drugconcentration attained by the formulation as well as the maintenance ofa high drug concentration. In one embodiment, the matrix material is aconcentration-enhancing polymer, as defined herein below.

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

The erodible matrix polymer may contain a wide variety of the same typesof additives and excipients known in the pharmaceutical arts, includingosmopolymers, osmagens, solubility-enhancing or -retarding agents andexcipients that promote stability or processing of the formulation.

The formulation may comprise an excipient that is a swellable materialsuch as a hydrogel in amounts that can swell and expand. Examples ofswellable materials include polyethylene oxide, hydrophilic polymersthat are lightly cross-linked, such cross-links being formed by covalentor ionic bond, which interact with water and aqueous biological fluidsand swell or expand to some equilibrium state. Swellable materials suchas hydrogels exhibit the ability to swell in water and retain asignificant fraction of water within its structure, and whencross-linked they will not dissolve in the water. Swellable polymers canswell or expand to a very high degree, exhibiting a 2 to 50 fold volumeincrease. Specific examples of hydrophilic polymeric materials includepoly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionicand cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol)having a low acetate residual and cross-linked with glyoxal,formaldehyde, or glutaraldehyde, methyl cellulose cross-linked withdialdehyde, a mixture of cross-linked agar and carboxymethyl cellulose,a water insoluble, water-swellable copolymer produced by forming adispersion of finely divided copolymer of maleic anhydride with styrene,ethylene, propylene, butylene, or isobutylene cross-linked with from0.001 to about 0.5 moles of a polyunsaturated cross-linking agent permole of maleic anhydride in the copolymer, water-swellable polymers ofN-vinyl lactams, cross-linked polyethylene oxides, and the like. Otherexamples of swellable materials include hydrogels exhibiting across-linking of 0.05 to 60%, hydrophilic hydrogels known as Carbopolacidic carboxy polymer, Cyanamer™ polyacrylamides, cross-linkedwater-swellable indene-maleic anhydride polymers, Good-rite™ polyacrylicacid, starch graft copolymers, Aqua-Keeps.™ acrylate polymer, diestercross-linked polyglucan, and the like.

The formulations may comprise additives such as polyethylene oxidepolymers, polyethylene glycol polymers, cellulose ether polymers,cellulose ester polymers, homo- and copolymers of acrylic acidcross-linked with a polyalkenyl polyether, poly(meth)acrylates,homopolyers (e.g., polymers of acrylic acid crosslinked with allylsucrose or allyl pentaerythritol), copolymers (e.g., polymers of acrylicacid and C₁₀-C₃₀ alkyl acrylate crosslinked with allyl pentaerythritol),interpolymers (e.g., a homopolymer or copolymer that contains a blockcopolymer of polyethylene glycol and a long chain alkyl acid ester),disintegrants, ion exchange resins, polymers reactive to intestinalbacterial flora (e.g., polysaccharides such as guar gum, inulin obtainedfrom plant or chitosan and chondrotin sulphate obtained from animals oralginates from algae or dextran from microbial origin) andpharmaceutical resins.

Polyalkylene Oxides

The pharmaceutical composition of the invention may comprise at leastone polyalkylene oxide having an average molecular weight of no morethan about 300,000 may be a polyethylene oxide, a polymethylene oxide, apolypropylene oxide, or a copolymer thereof. In exemplary embodiments,the first polyalkylene oxide is a polyethylene oxide. In someembodiments, the polyalkylene oxide, which may be polyethylene oxide,has an average molecular weight of about 300,000. In other embodiments,the polyalkylene oxide, which may be polyethylene oxide, has an averagemolecular weight of about 200,000. In specific embodiments, thepolyalkylene oxide, which may be polyethylene oxide, has an averagemolecular weight of about 100,000.

In exemplary embodiments, the pharmaceutical composition of theinvention may comprise polyalkylene oxide having an average molecularweight of at least 1,000,000 may be a polyethylene oxide, apolymethylene oxide, a polypropylene oxide, or a copolymer thereof. Inexemplary embodiments, the polyalkylene oxide is a polyethylene oxide.In some embodiments, the second polyalkylene oxide, which may bepolyethylene oxide, has an average molecular weight of about 2,000,000.In other embodiments, the polyalkylene oxide, which may be polyethyleneoxide, has an average molecular weight of about 4,000,000. In furtherembodiments, the second polyalkylene oxide, which may be polyethyleneoxide, has an average molecular weight of about 5,000,000. In stillother embodiments, the polyalkylene oxide, which may be polyethyleneoxide, has an average molecular weight of about 7,000,000. In additionalembodiments, the polyalkylene oxide, which may be polyethylene oxide,has an average molecular weight of about 8000,000. In other embodiments,the polyalkylene oxide, which may be polyethylene oxide, has an averagemolecular weight of about 15,000,000.

In exemplary embodiments, the polymer may be selected from the groupcomprising polyalkylene oxides, preferably polymethylene oxide,polyethylene oxide, polypropylene oxide; polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymersthereof, and mixtures of at least two of the stated polymers.

In exemplary embodiments, the polymer may be a water-soluble polymer foruse either as a base polymer material or as a dissolution modifyingagent such as polyethylene oxide (PEO), for example the brand namePOLYOX® (Dow). It is recognized that the thermoplastic polymers may beused in varying molecular weights, such as 100K, 200K, 300K, 400K, 600K,900K, 1000K, 2000K, 4000K, 5000K, 7000K and 8000K (K=1,000), andoptionally combinations thereof. In a preferred embodiment, the PEO is ahigh molecular weight PEO. In a preferred embodiment, the PEO has amolecular weight of about 7,000,000. In a preferred embodiment, the PEOhas a molecular weight between about 4,000,000 and 8,000,000. Examplesof polyethylene oxide include POLYOX water soluble resin, which islisted in the NF and has approximate molecular weights which range from100,000 to about 8,000,000. A preferred polyethylene oxide is POLYOXWSR-80, POLYOX WSR N-750, POLYOX WSR-205, POLYOX WSR-1105, POLYOX WSRN-12K, POLYOX WSR N-60K, WSR-301, WSR Coagulant, WSR-303, andcombinations thereof.

The amount of polyalkylene oxide present in the pharmaceuticalcomposition can and will vary and in general, the amount of thepolyalkylene oxide present in the pharmaceutical composition may rangefrom about 10% to about 95% by weight of the composition. In variousembodiments, the amount of the polyalkylene oxide present in thepharmaceutical composition may range from about 20% to about 90%, fromabout 30% to about 80%, or from about 35% to about 70% by weight of thepharmaceutical composition. In various embodiments, the amount of thepolyalkylene oxide present in the pharmaceutical composition may beabout 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

In the above described embodiments high molecular weight polyethyleneoxide having, based on rheological measurements, an approximatemolecular weight of from 2,000,000 to 15,000,000 or from 2,000,000 to8,000,000 may be used. In particular polyethylene oxides having, basedon rheological measurements, an approximate molecular weight of2,000,000, 4,000,000, 7,000,000 or 8,000,000 may be used. In particularpolyethylene oxides having, based on rheological measurements, anapproximate molecular weight of 4,000,000, may be used.

In embodiments wherein the composition further comprises at least onelow molecular weight polyethylene oxide is used polyethylene oxideshaving, based on rheological measurements, an approximate molecularweight of less than 1,000,000, such as polyethylene oxides having, basedon rheological measurements, an approximate molecular weight of from100,000 to 900,000 may be used. The addition of such low molecularweight polyethylene oxides may be used to specifically tailor therelease rate such as enhance the release rate of a formulation thatotherwise provides a release rate to slow for the specific purpose. Insuch embodiments at least one polyethylene oxide having, based onrheological measurements, an approximate molecular weight of 100,000 maybe used.

In certain such embodiments the composition comprises at least onepolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of at least 1,000,000 and at least onepolyethylene oxide having, based on rheological measurements, anapproximate molecular weight of less than 1,000,000, wherein thecomposition comprises at least about 10% (by wt) or at least about 20%(by wt) of the polyethylene oxide having, based on rheologicalmeasurements, an approximate molecular weight of less than 1,000,000. Incertain such embodiments the curing temperature is less than about 80°C. or even less than about 77° C. In certain embodiments the overallcontent of polyethylene oxide in the composition is at least about 80%(by wt).

Lubricant

In exemplary embodiments, the pharmaceutical composition of theinvention may include lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof and other tableting aids such a magnesium stearateand microcrystalline cellulose

The pharmaceutical compositions disclosed herein may also furthercomprise at least one lubricant, which facilitates preparation of soliddosage forms of the pharmaceutical composition. Non-limiting examples ofsuitable lubricants include magnesium stearate, calcium stearate, zincstearate, colloidal silicon dioxide, hydrogenated vegetable oils,sterotex, polyoxyethylene monostearate, polyethylene glycol, sodiumstearyl fumarate, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, and light mineral oil. In exemplary embodiments, thelubricant may be magnesium stearate.

In embodiments in which the lubricant is included in the pharmaceuticalcomposition, the amount of the lubricant may range from about 0.1% toabout 3% by weight of the pharmaceutical composition. In variousembodiments, the amount of the lubricant may range from about 0.1% toabout 0.3%, from about 0.3% to about 1%, or from about 1% to about 3% byweight of the pharmaceutical composition. In exemplary embodiments, theamount of the lubricant may be about 1% by weight of the pharmaceuticalcomposition.

Coating

The pharmaceutical composition can be coated with one or more entericcoatings, seal coatings, film coatings, barrier coatings, compresscoatings, fast disintegrating coatings, or enzyme degradable coatings.

In some cases, the formulation disclosed herein is coated with a coatingmaterial, e.g., a sealant. In some embodiments, the coating material iswater soluble. In some embodiments, the coating material comprises apolymer, plasticizer, a pigment, or any combination thereof. In someembodiments, the coating material is a form of a film coating, e.g., aglossy film, a pH independent film coating, an aqueous film coating, adry powder film coating (e.g., complete dry powder film coating), or anycombination thereof. In some embodiments, the coating material is highlyadhesive. In some embodiments, the coating material provides low levelof water permeation. In some embodiments, the coating material providesoxygen barrier protection. In some embodiments, the coating materialallows immediate disintegration for fast release of drug actives. Insome embodiments, the coating material is pigmented, clear, or white. Insome embodiments, the coating material is clear. Exemplary coatingmaterials include, without limitation, polyvinyl alcohol (PVA),cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP),methacrylic acid copolymers, cellulose acetate trimellitate (CAT),hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose (HPMC), hydroxy propyl methyl cellulose acetatesuccinate (hypromellose acetate succinate), shellac, sodium alginate,and zein. In some embodiments, the coating material comprises or is PVA.In some embodiments, the coating material comprises or is HPMC. Anexemplary PVA-based coating material includes Opadry II. In someinstances, the coating material is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10% of the weight of the formulation. In some instances, the coatingmaterial represent between about 1% and about 15% of the total weight ofeach first particulate, including, but not limited to, between about 5%and about 10%, between about 6% and about 10%, between about 7% andabout 10%, between about 8% and about 10%, or between about 9% and about10%. In some instances, the coating material is greater than about 2%,greater than about 3%, greater than about 4%, greater than about 5%,greater than about 6%, greater than about 7%, greater than about 8%,greater than about 9%, or greater than about 10% of the weight of theformulation. In some instances, the coating material is less than about2%, less than about 3%, less than about 4%, less than about 5%, lessthan about 6%, less than about 7%, less than about 8%, less than about9%, or less than about 10% of the weight of the formulation.

Multiple coatings can be applied for desired performance. Further, thedosage form can be designed for immediate release, pulsatile release,controlled release, extended release, delayed release, targeted release,synchronized release, or targeted delayed release. Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The definitions of theseterms are known to those skilled in the art. In addition, the dosageform release profile can be affected by a polymeric matrix composition,a coated matrix composition, a multiparticulate composition, a coatedmultiparticulate composition, an ion-exchange resin-based composition,an osmosis-based composition, or a biodegradable polymeric composition.Without wishing to be bound by theory, it is believed that the releasemay be effected through favorable diffusion, dissolution, erosion,ion-exchange, osmosis or combinations thereof.

Dosage forms of the invention can further be coated with, for example, aseal coating, an enteric coating, an extended release coating, or atargeted delayed release coating. These various coatings are known inthe art, but for clarity, the following brief descriptions are provided:seal coating, or coating with isolation layers: Thin layers of up to 20microns in thickness can be applied for variety of reasons, includingfor particle porosity reduction, to reduce dust, for chemicalprotection, to mask taste, to reduce odor, to minimize gastrointestinalirritation, etc. The isolating effect is proportional to the thicknessof the coating. Water soluble cellulose ethers are preferred for thisapplication. HPMC and ethyl cellulose in combination, or Eudragit E100,may be particularly suitable. In exemplary embodiments, the coating maybe OPADRY® Y-1-7000, a coating ready mix from Colorcon. Opadry Y-1-7000contains hypromellose 5 cP, titanium dioxide and macrogol/PEG 400.Traditional enteric coating materials listed elsewhere can also beapplied to form an isolating layer.

Optionally, the sustained-release matrix multiparticulate systems,tablets, or capsules can be coated with a sustained release coating suchas the sustained release coatings described herein. Such coatingspreferably include a sufficient amount of hydrophobic and/or hydrophilicsustained-release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greater depending upon,e.g., the desired release rate. In certain embodiments, a sustainedrelease coating is applied to the sustained release spheroids, granules,or matrix multiparticulates. In such embodiments, the sustained-releasecoating may include a water insoluble material such as (a) a wax, eitheralone or in admixture with a fatty alcohol; or (b) shellac or zein. Thecoating is preferably derived from an aqueous dispersion of thehydrophobic sustained release material.

In other preferred embodiments of the present invention, the sustainedrelease material comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art as fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. In order to obtain a desirable dissolution profile, itmay be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties, such as different molarratios of the quaternary ammonium groups to the neutral (meth)acrylicesters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm GMBH andCo. Kg Darmstadt, Germany. There are several different types ofEudragit®. For example, Eudragit E is an example of a methacrylic acidcopolymer which swells and dissolves in acidic media. Eudragit L is amethacrylic acid copolymer which does not swell at about pH<5.7 and issoluble at about pH>6. Eudragit S does not swell at about pH<6.5 and issoluble at about pH>7. Eudragit RL and Eudragit RS are water swellable,and the amount of water absorbed by these polymers is pH-dependent;however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available under theTradenames Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit®RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylicesters with a low content of quaternary ammonium groups, the molar ratioof ammonium groups to the remaining neutral (meth)acrylic esters being1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecularweight is about 150,000. The code designations RL (high permeability)and RS (low permeability) refer to the permeability properties of theseagents. Eudragit® RL/RS mixtures are insoluble in water and in digestivefluids. However, coatings formed from the same are swellable andpermeable in aqueous solutions and digestive fluids.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used. Methylcitrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Extended release coatings are designed to effect delivery over anextended period of time. The extended release coating is apH-independent coating formed of, for example, ethyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, acrylic esters, or sodium carboxymethylcellulose. Various extended release dosage forms can be readily designedby one skilled in art to achieve delivery to both the small and largeintestines, to only the small intestine, or to only the large intestine,depending upon the choice of coating materials and/or coating thickness.

Enteric coatings are mixtures of pharmaceutically acceptable excipientswhich are applied to, combined with, mixed with or otherwise added tothe carrier or composition. The coating may be applied to a compressedor molded or extruded tablet, a gelatin capsule, and/or pellets, beads,granules or particles of the carrier or composition. The coating may beapplied through an aqueous dispersion or after dissolving in appropriatesolvent.

In certain embodiments, the pharmaceutical composition, upon oraladministration to a human or non-human patient in need thereof, providescontrolled release for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 14, 16, 18, 20, 24, 36, 48, 72, 96, 120, 144, or 168 hours.

The term “sustained release” refers release of a drug from its dosageform (e.g., tablet) at such a rate that its blood levels are maintainedwithin the therapeutic range (i.e., at or above minimum effectiveconcentration (MEC)) but below toxic levels over an extended period oftime (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20,22, 24, 36, 48, 72, 96, 120, 144, or 168 hours or greater). The term“sustained release” may be used interchangeably with “slow-release,”“controlled release,” or “extended release.” The sustained releaseproperty of a dosage form is typically measured by an in vitrodissolution method and confirmed by an in vivo blood concentration-timeprofile (i.e., a pharmacokinetic profile).

In certain embodiments, the pharmaceutical compositions of the presentinvention release about 90% to 100% of their pharmaceutically activeagents in a linear or near linear fashion for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 36, 48, 72, 96, 120, 144, or 168 hours in an in vitro dissolutionanalysis.

Delayed release generally refers to the delivery so that the release canbe accomplished at some generally predictable location in the lowerintestinal tract more distal to that which would have been accomplishedif there had been no delayed release alterations. The preferred methodfor delay of release is coating. Any coatings should be applied to asufficient thickness such that the entire coating does not dissolve inthe gastrointestinal fluids at pH below about 5, but does dissolve at pHabout 5 and above. It is expected that any anionic polymer exhibiting apH-dependent solubility profile can be used as an enteric coating in thepractice of the present invention to achieve delivery to the lowergastrointestinal tract. Polymers for use in the present invention areanionic carboxylic polymers.

In exemplary embodiments, the coating may comprise shellac, also calledpurified lac, a refined product obtained from the, resinous secretion ofan insect. This coating dissolves in media of pH>7.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants,stabilizers such as hydroxy propyl cellulose, acid/base may be added tothe coatings besides plasticizers to solubilize or disperse the coatingmaterial, and to improve coating performance and the coated product.

Pharmaceutical Dosage Forms

The compositions of the present invention can be processed byagglomeration, air suspension chilling, air suspension drying, balling,coacervation, coating, comminution, compression, cryopelletization,encapsulation, extrusion, wet granulation, dry granulation,homogenization, inclusion complexation, lyophilization, melting,microencapsulation, mixing, molding, pan coating, solvent dehydration,sonication, spheronization, spray chilling, spray congealing, spraydrying, or other processes known in the art. The compositions can beprovided in the form of a minicapsule, a capsule, a tablet, an implant,a troche, a lozenge (minitablet), a temporary or permanent suspension,an ovule, a suppository, a wafer, a chewable tablet, a quick or fastdissolving tablet, an effervescent tablet, a buccal or sublingual solid,a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, atriturate, a platelet, a strip or a sachet. Compositions can also beadministered as a “dry syrup”, where the finished dosage form is placeddirectly on the tongue and swallowed or followed with a drink orbeverage. These forms are well known in the art and are packagedappropriately. The compositions can be formulated, for example, fororal, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical orrectal delivery.

The pharmaceutical composition can be coated with one or more entericcoatings, seal coatings, film coatings, barrier coatings, compresscoatings, fast disintegrating coatings, or enzyme degradable coatings.Multiple coatings can be applied for desired performance. Further, thedosage form can be designed for immediate release, pulsatile release,controlled release, extended release, delayed release, targeted release,synchronized release, or targeted delayed release. Forrelease/absorption control, solid carriers can be made of variouscomponent types and levels or thicknesses of coats, with or without anactive ingredient. Such diverse solid carriers can be blended in adosage form to achieve a desired performance. The definitions of theseterms are known to those skilled in the art. In addition, the dosageform release profile can be affected by a polymeric matrix composition,a coated matrix composition, a multiparticulate composition, a coatedmultiparticulate composition, an ion-exchange resin-based composition,an osmosis-based composition, or a biodegradable polymeric composition.Without wishing to be bound by theory, it is believed that the releasemay be effected through favorable diffusion, dissolution, erosion,ion-exchange, osmosis or combinations thereof.

In carrying out the method of the present invention, the compositions ofthe invention may be administered to mammalian species, such as dogs,cats, humans, etc. and as such may be incorporated in a conventionalsystemic dosage form, such as a tablet, capsule, elixir or injectable.The above dosage forms will also include the necessary carrier material,excipient, lubricant, buffer, antibacterial, bulking agent (such asmannitol), anti-oxidants (ascorbic acid of sodium bisulfite) or thelike.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The pharmaceutical compositions of the invention may be administered inthe dosage forms in single or divided doses of one to four times daily.It may be advisable to start a patient on a low dose combination andwork up gradually to a high dose combination.

Liquid formulations can be prepared by dissolving or suspending one orthe combination of active substances in a conventional liquid vehicleacceptable for pharmaceutical administration so as to provide thedesired dosage in one to four teaspoonful.

Dosage forms can be administered to the patient on a regimen of, forexample, one, two, three, four, five, six, or other doses per day. Thecompositions of the invention as described herein may be administered,for example, for one day, two days, three days, four days, five days,six days, a week, two weeks, three weeks, four weeks, five weeks, sixweeks, a month, two months, three months, four months, or more. Thecompositors of the invention as described herein may be administered,for example, for a prolonged period, that is, for as long as thepotential for a disease or condition remains and/or the symptomscontinue.

In order to more finely regulate the dosage schedule, the activesubstances may be administered separately in individual dosage units atthe same time or carefully coordinated times. Since blood levels arebuilt up and maintained by a regulated schedule of administration, thesame result is achieved by the simultaneous presence of the twosubstances. The respective substances can be individually formulated inseparate unit dosage forms in a manner similar to that described above.

In formulating the compositions, the active substances, in the amountsdescribed above, may be compounded according to accepted pharmaceuticalpractice with a physiologically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in the particular typeof unit dosage form.

The liquid formulations useful herein may comprise a solvent, solution,suspension, microsuspension, nanosuspension, emulsion, microemulsion,gel or even a melt containing the active component or components. Insome embodiments the nanoparticles, nanofibers, or nanofibrils may be inthe form of, or within or on, granules, powders, suspensions, solutions,dissolvable films, mats, webs, tablets, or releasable forms particularlyreleasable dosage forms. Other particular useful forms are concentratesto which a diluting liquid is added prior to use. The product may alsobe sprayed onto the inner surface of a container to which a liquid isadded later prior to use and the nanoparticles, nanofibers, ornanofibrils, are released into the liquid. Pharmaceutical compositionsof the present invention can include nanoparticles, compositenanoparticles, nanosuspension, or nanocapsules of the present invention.

The composition may also include various antioxidants to retardoxidation of one or more active ingredient or nanoparticles, compositenanoparticles, nanosuspension, or nanocapsules. The prevention of theaction of microorganisms can be brought about by preservatives such asvarious antibacterial and antifungal agents, including but not limitedto parabens (e.g., methylparabens, propylparabens), chlorobutanol,phenol, sorbic acid, thimerosal or combinations thereof.

In order to increase the effectiveness of a treatment with thenanoparticles, nanogels, composite nanoparticles, nanosuspension, ornanocapsules of the present invention, it may be desirable to combinethese nanoparticles, composite nanoparticles, or nanocapsules with othertherapies effective in the treatment of a particular disease orcondition.

The formulations as described above may be administered for a prolongedperiod, that is, for as long as the potential for a disease or conditionremains or the symptoms continue.

In certain such embodiments of the invention the formulation has ahardness or cracking force of at least about 110 N, preferably of atleast about 120 N, at least about 130 N or at least about 140 N, morepreferably of at least about 150 N, at least about 160 N or at leastabout 170 N, most preferably of at least about 180 N, at least about 190N, at least about 200 N, at least about 210 N, at least about 220 N, atleast about 230 N, at least about 240 N, or at least about 250 N.

Packaging/Treatment Kits

The present invention relates to a kit for conveniently and effectivelycarrying out the methods in accordance with the present invention. Sucha kit may include a number of unit dosages. Such kits can include ameans for containing the dosages oriented in the order of their intendeduse. An example of a means for containing the dosages in the order oftheir intended uses is a card. An example of such a kit is a “blisterpack”. Blister packs are well known in the packaging industry and arewidely used for packaging pharmaceutical unit dosage forms. If desired,the blister can be in the form of a childproof blister, i.e., a blisterthat is difficult for a child to open, yet can be readily opened by anadult. If desired, a memory aid can be provided, for example in the formof numbers, letters, or other markings or with a calendar feature and/orcalendar insert, designating the days and the sections of a day in thetreatment schedule in which the dosages can be administered, such as anAM dose is packaged with a “mid day” and a PM dose; or an AM dose ispackaged with a PM dose. Alternatively, placebo dosages, or vitamin ordietary supplements, either in a form similar to or distinct from thepharmaceutical active dosages, can be included.

As discussed herein, the products of manufacture of the invention cancomprise the packaging of the therapeutic drug combinations of theinvention, alone or in combination, as “blister packages” or as aplurality of packettes, including as lidded blister packages, liddedblister or blister card or packets, or a shrink wrap.

Other means for containing said unit dosages can include bottles andvials, wherein the bottle or vial comprises a memory aid, such as aprinted label for administering said unit dosage or dosages. The labelcan also contain removable reminder stickers for placement on a calendaror dayminder to further help the patient to remember when to take adosage or when a dosage has been taken.

Administration

The pharmaceutical compositions may be optimized for particular types ofdelivery. For example, pharmaceutical compositions for oral delivery areformulated using pharmaceutically acceptable carriers that are wellknown in the art. The carriers enable the agents in the composition tobe formulated, for example, as a tablet, pill, capsule, solution,suspension, sustained release formulation; powder, liquid or gel fororal ingestion by the subject.

The liquid or solid compositions may contain suitable pharmaceuticallyacceptable excipients as set out above. Preferably the compositions areadministered by the oral, intranasal or respiratory route for local orsystemic effect. Compositions in preferably sterile pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device may be attached to a face mask, tent or intermittentpositive pressure breathing machine. Solution, suspension or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

Alternatively, the composition may be applied intermittently, or in apulsed manner. Accordingly, an alternative embodiment of the inventionis to apply the composition on an intermittent or pulsed dosageschedule. For example, the composition of the invention may be used fortwo or more days, stopped, then restarted again at a time from between 2weeks to 3 months later, and at even more long-spaced intervals.

Dosages of the pharmaceutical composition of the invention are forexample, 0.5 mg, 1.0 mg, 2.0 mg, 5.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg,300 mg, 350 mg, 400 mg, 500 mg, 600 mg, and can be administered, forexample, once daily, twice daily, three times daily, four times daily.

The treatments may include various “unit doses.” Unit dose is defined ascontaining a predetermined-quantity of the therapeutic composition. Thequantity to be administered, and the particular route and formulation,are within the skill of those in the clinical arts. A unit dose need notbe administered as a single injection but may comprise continuousinfusion over a set period of time. Alternatively, the amount specifiedmay be the amount administered as the average daily, average weekly, oraverage monthly dose.

Hardness

In certain embodiments, the present invention is directed to a solidoral extended release pharmaceutical dosage form comprising an extendedrelease matrix formulation, the extended release matrix formulationcomprising

a composition comprising:

-   -   (1) at least one polyethylene oxide having, based on rheological        measurements, an approximate molecular weight selected from the        group consisting of at least about 1,000,000; at least about        2,000,000; at least about 3,000,000; at least about 4,000,000;        at least about 5,000,000; at least about 6,000,000; at least        about 6,000,000; at least about 7,000,000; and at least about        8,000,000; and    -   (2) at least one active agent; and

wherein the extended release matrix formulation when subjected to anindentation test has a “hardness” of at least about 200 N.

In certain such embodiments of the invention the extended release matrixformulation has a hardness or cracking force of at least about 110 N,preferably of at least about 120 N, at least about 130 N or at leastabout 140 N, more preferably of at least about 150 N, at least about 160N or at least about 170 N, most preferably of at least about 180 N, atleast about 190 N, at least about 200 N, at least about 210 N, at leastabout 220 N, at least about 230 N, at least about 240 N, or at leastabout 250 N.

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLES Example 1

Ketamine Sustained-release Tablets 60 mg Formulation

Excipients mg/tablet % (w/w) Ketamine HCl 69.20 16.80 Polyethylene Oxide326.80 79.32 Magnesium Stearate 4.00 0.97 Opadry White Y-1-7000(Coating) 12.00 2.91 Total 412.00 100.00

Manufacturing Steps:

-   -   1. Mix ketamine HCl with polyethylene oxide in a suitable mixer        until uniformed.    -   2. Blend magnesium stearate into the above dry powder mixture.    -   3. Compress the final powder blend into tablets with aim tablet        mass of 400 mg and aim tablet hardness of 210 N.    -   4. Perform initial coating to protect tablets from damage in        next step of tablets curing.    -   5. Cure tablets at the temperature range of 70° C. to 75° C. to        achieve desired firmness.    -   6. Continue to coat tablets from above step to gain sufficient        weight.

Example 2

Study ZPS-603 (Study 603) was a hybrid study design with 4 cohorts andmultiple study objectives. The objectives of Cohorts 1, 2 and 3 were toevaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) ofan extended release ketamine oral formulation in healthy volunteersafter single dose and multiple doses. The design was a double-blind,placebo-controlled single and multiple ascending dose study in healthyvolunteers. Doses were 60 mg, 120 mg and 240 mg for Cohorts 1, 2 and 3respectively. Each dose level was initially given as a single dose, thenone week later as 5 doses given at 12 hour intervals. Endpoints includedsafety, tolerability, ketamine and norketamine PK, and PD (suicidalityassessments, and dissociative symptom rating scale scores).

The objective of Cohort 4 was to evaluate efficacy, safety, PK and PD ofan extended release ketamine oral formulation in patients withtreatment-resistant depression and/or treatment-resistant anxiety(TRD/TRA). Patients were selected based on prior demonstrated moodresponse to subcutaneous ketamine, and clinically significant scores onthe Montgomery Asberg Depression Rating Scale (MADRS; Montgomery 1979)and/or the Hamilton Anxiety Scale (HAMA; Hamilton 1959). The design wasan open label multiple ascending dose study. The initial dose was 60 mg,and could be escalated by an additional 60 mg 12 hourly, based onassessment of mood symptoms, to a maximum dose of 240 mg, with a totalof 7 doses given 12 hourly between 0 and 72 hours. Endpoints includedsafety, tolerability, ketamine and norketamine PK, and PD (mood ratingsincluding the Fear Questionnaire (FQ; Marks 1979), HAMA and MADRS, anddissociative symptom rating scale scores).

A protocol amendment added a further objective to Cohort 4, namely toevaluate the safety and efficacy of up to 3 months dosing of theextended release ketamine oral formulation in patients with TRD/TRA, whoresponded to treatment in the initial 96 hour ascending dose phase ofZPS-603, in an open-label extension (OLE) treatment phase. Endpoints forthe OLE were similar to those of the initial 96 hour ascending dosephase of ZPS-603.

Results, Cohorts 1-3: Demographics:

Mean (SD) parameters for Cohort 1-3 participants are shown in Table 1.One subject in Cohort 2 (#16) withdrew from the study between single andmultiple dosing, for reasons unrelated to safety/tolerability.

TABLE 1 Demographic parameter Cohort 1 Cohort 2 Cohort 3 Ketamine dose60 mg 120 mg 240 mg N ketamine/placebo 6/2 6/2 6/2 Dropouts 0 1 0 Age(years) 27 ± 10 23 ± 3 21 ± 1 Number of Males/Females 6/2 7/1 5/3 Weight(kg) 83.8 ± 10.2 74.9 ± 9.7 68.9 ± 6.7 Height (cm) 1.80 ± 0.09  1.76 ±0.07  1.73 ± 0.07 BMI (kg/m²) 25.9 ± 1.5  24.2 ± 2.1 23.1 ± 1.3

Safety:

There were no changes of clinical significance in vital signs, ECGs,safety laboratory tests or urinalyses in any subjects in Cohorts 1-3during or after study completion.

Tolerability:

Adverse events reported by study group are shown in Table 2. The onlyadverse event to show dose-related increases in frequency wasdissociation, in subjects dosed with 240 mg.

Cohort 1 Cohort 2 Cohort 3 All cohorts Adverse event (60 mg) (120 mg)(240 mg) (Placebo) Vascular disorders Syncope 0 0 0 1 Dizziness 0 1 1 0Respiratory, thoracic and mediastinal disorders Throat irritation 1 0 00 epistaxis 1 0 0 0 Psychiatric disorders Restlessness 1 0 0 0Dissociation 0 0 11 2 Nervous system disorders Headache 2 0 1 0Gastrointestinal disorders Nausea 0 0 1 0 General disorders andadministration site conditions Swelling at 0 0 0 1 catheter site Total 51 14 4

Pharmacodynamics:

CADS S: Mean CADS S scores over time are shown in FIG. 2. Minorincreases were noted at 3 hours after single dosing in Cohorts 1 and 3(FIG. 2A), and at 3-12 hours after the first dose in the multiple dosephase for Cohort 3(FIG. 2B). (It should be noted that the maximum scoreon this scale is 84 points and that these are minimal changes comparedwith subcutaneous or IV ketamine dosing).

Suicidality Ratings: No participants reported suicidal ideation at anytime in Cohorts 1-3, as assessed by the Columbia Suicide Severity RatingScale.

Pharmacokinetics:

FIG. 3 shows mean concentration-time profiles of ketamine andnorketamine after single and multiple doses of 60, 120 and 240 mg.Concentrations of both analytes were relatively stable for 5-10 hoursafter dosing, consistent with the sustained release characteristics ofthe tablet. Norketamine concentrations were approximately 10-fold higherthan ketamine concentrations in both plots, reflecting extensive firstpass metabolism after oral dosing. For all 3 cohorts, ketamine andnorketamine pharmacokinetic parameters appeared to follow first orderkinetics, specifically AUC and Cmax were dose proportional after singleand multiple doses of ketamine 60 mg, 120 mg and 240 mg extended releasetablets (FIG. 4). There appeared to be evidence of autoinduction, inthat the multiple dose AUC₀₋₁₂ values for both ketamine and norketaminewere less than the single dose AUC 0-∞, and the ratio of these decreasedin a dose-related manner (see Table 3). The mechanism for inductionappears to be via CYP2B6. Ketamine induces activity of CYP2B6 (Chen2010), and is itself metabolized by this enzyme.

TABLE 3 Ketamine AUC Cmax SD¹ MD² MD² Dose (0-∞) (0-12) Ratio³ SD¹(0-12) Ratio³  60 mg 79.24 74.18 0.94 9.71 11.91 1.23 120 mg 196.92133.11 0.68 16.40 20.66 1.26 240 mg 384.58 217.41 0.57 37.98 41.57 1.09

TABLE 4 Single and multiple dose AUC and Cmax for ketamine (upper panel)and norketamine (lower panel), and ratios. MD/SD AUC ratios less than 1are suggestive of autoinduction (bolded). Norketamine AUC Cmax SD¹ MD²MD² Dose (0-∞) (0-12) Ratio³ SD¹ (0-12) Ratio³  60 mg 872.21 980.54 1.1273.74 124.65 1.69 120 mg 2133.09 1697.06 0.80 161.24 229.91 1.43 240 mg4079.19 3019.81 0.74 314.67 421.11 1.34 ¹Single Dose ²Multiple Dose³Ratio = MD/SD.

Results, Cohort 4: Demographics:

Mean (SD) parameters for Cohort 4 participants are shown in Table 5.

TABLE 5 Demographic parameter Cohort 1 Dropouts 0 Age (years) 27 ± 4 Number of Males/Females 4/3 Weight (kg) 82.1 ± 22.3 Height (cm) 1.75 ±0.07 BMI (kg/m²) 26.5 ± 5.6 

Diagnoses:

All 7 patients had current diagnoses of Social Anxiety Disorder. Fivealso had diagnoses of Major Depressive Disorder (MDD), and one hadcomorbid Generalized Anxiety Disorder. At screening, mean HAMA score was22.9 (consistent with moderate severity) and mean FQ score was 48.4(approximately 2-fold higher than the non-clinical population mean).Mean MADRS score in the 5 patients with MDD was 31.2 (consistent withmoderate depression).

Dosing:

On Day 1 all 7 patients were dosed with 1×60 mg tablets in the morning.All 7 patients received 2×60 mg tablets at 12 hours, and all 7 patientsreceived 3×60 mg tablets at 24 hours. At 36 hours 2 patients received3×60 mg tablets and 5 patients received 4×60 mg tablets. At 48 hours, 1patient received 3×60 mg tablets and 6 patients received 4×60 mgtablets. At 56 and 72 hours all 7 patients received 4×60 mg tablets (seeTable 6).

TABLE 6 Patient ID Day 1 Day 2 Day 3 Day 4 (mg) (mg) (mg) (mg) am pm ampm am pm am 039-25 60 120 180 180 180 240 240 042-26 60 120 180 240 240240 240 040-27 60 120 180 240 240 240 240 043-28 60 120 180 240 240 240240 041-29 60 120 180 180 240 240 240 038-30 60 120 180 240 240 240 240044-32 60 120 180 240 240 240 240

Safety:

There were no changes of clinical significance in vital signs, ECGs,safety laboratory tests or urinalyses in any subjects in Cohort 4 duringor after study completion.

Tolerability:

Adverse events reported by Cohort 4 are shown in Table 7. Overall,single and multiple doses of the extended release ketamine tablets werewell tolerated.

TABLE 7 Adverse Events (total no. AEs reported/subject n) Cohort 4Feeling spaced out 1/1 Headache 3/3 Lightheadedness 1/1

Pharmacodynamics: CADSS:

Mean CADSS scores over time are shown in FIG. 5A. Mean CADSS scorestended to decrease over time. This contrasts markedly from the change inCADSS scores after subcutaneous (SC) ketamine. FIG. 5B shows mean CADSSscores up to 3 hours after oral and SC dosing, in six of seven Cohort 4participants with both sets of data. Overall, multiple dose oralketamine was not associated with dissociative symptoms, as evaluated bythe CADSS scale.

Anxiety Rating Scales: HAMA and FQ:

Individual and group mean HAMA and FQ scores by timepoint are shown inFIG. 6 (6A: HAMA; 6B: FQ) There was a consistent trend for both scoresto decrease over time, most noticeably in patients with higher baselinescores. The trend for gradual improvement in anxiety contrasts markedlyfrom the rapid reduction in anxiety scores after subcutaneous (SC)ketamine. FIG. 7 shows mean HAMA scores after oral and SC dosing, in sixof seven Cohort 4 participants with both sets of data. All sevenparticipants were assessed to be treatment responders (>50% reduction)based on changes in HAMA scores, and six of seven participants wereresponders based on changes in FQ scores.

MADRS:

Individual and group mean MADRS scores by timepoint are shown in FIG. 8.There was a consistent trend for scores to decrease over time, mostnoticeably in patients with higher baseline scores. All sevenparticipants were assessed to be treatment responders (>50% reduction)based on change in MADRS scores. Subject 042-026 reported worseningsymptoms of depression at 48 and 72 h, without changes in ratings ofanxiety. After discussion with clinic staff he reported that these wererelated to feelings of sadness at his experience of being excluded fromgroup activities, rather than substantial and persistent changes in moodsuggestive of a relapse of major depression. Following this discussionhis MADRS scores fell again.

FIG. 9 shows smoothed mean depression (MADRS; 9A) and anxiety (FQ, HAMA;9B and C) scores in 3 patients in Cohort 4, who entered a subsequent 3month open-label extension (OLE) phase. All three patients reportedimprovements in mood ratings during this time. Mean depression ratingsappeared to take 6 weeks for maximal improvement (FIG. 9A), whereas meanmaximal anxiety scale improvement appeared to occur by week 2 (FIGS. 9B,9C).

Pharmacokinetics:

FIG. 10 shows mean concentration-time profiles of ketamine andnorketamine over 96 hours in Cohort 4. Dose-related increases in bothketamine and norketamine plasma concentrations were noted out to 48 h,as patients continued to take higher doses. Norketamine concentrationswere consistently higher than ketamine concentrations at all timepoints, reflecting extensive first pass metabolism. The data indicate alarge inter-subject and intra-subject variation in the PK profiles.

To assess the impact of repeated dosing on enzyme induction, individualketamine: norketamine (K:NK) ratios were calculated for each time point.These are plotted in FIG. 11. The mean ratio of K:NK was approximately11 at 0 h, and progressively decreased to approximately 5 at 96 h. Thecorrelation of K:NK ratios against time gave a coefficient ofdetermination (r²) of 0.26. Data variability (expressed as % coefficientof variation) also decreased during multiple dosing, from 44% at 0 h to23% at 96 h. These data are suggestive of increased first passmetabolism associated with repeat 12-hourly dosing, which appears toasymptote by 72 hours.

Example 3

Study 15/STH/86 was a hybrid study design with a preliminary acuteketamine dose response phase lasting 3-4 weeks, and a subsequent 3-monthmaintenance treatment phase. 24 patients with treatment-resistantanxiety disorders were dosed with 3 single ascending subcutaneous dosesof ketamine (0.25, 0.5, 1 mg/kg), and 12 also received a dose ofmidazolam 0.01 mg/kg. 20 patients participated in the maintenance phase,where ketamine 1 mg/kg was administered 1-2× weekly for up to 14 weeks.Study assessments included mood ratings using the Fear Questionnaire(FQ; Marks and Mathews 1979) before and after each ketamine dose. The FQscale includes a subscale that measures anxiety associated with BloodInjury (FQBI), a specific phobia.

Results:

25 patients participated in the acute dose-response phase and 20patients participated in the maintenance phase.

Anxiety Rating Scales—FQ Acute Dose-Response:

Baseline mean FQ Blood Injury (FQBI) scale score was 12.4. At 1 hourafter ketamine dosing, there were rapid dose-related decreases in meanscores (FIG. 12). These scores gradually returned towards baseline overthe next 168 h. The acute reduction and slow increase in scores weredose-related, with the higher ketamine doses having more durable effectscompared with the lowest 0.25 mg/kg dose. Changes in FQBI scores aftermidazolam were similar to those of the 0.5 mg/kg ketamine dose profiles.

Anxiety Rating Scales—FQ Acute Dose-Response:

Analysis of the relationship between ketamine and norketamineconcentrations at 2 hours and FQBI scores is shown in FIGS. 13A and 13Brespectively. Baseline FQBI scores are shown in red, with error barsrepresenting the standard deviation. Higher concentrations wereassociated with lower FQBI scores, with a stronger correlation noted fornorketamine compared with ketamine.

FQ Maintenance Treatment:

Week 1 subscale predose scores were modestly lower compared withsubscale scores at screening (i.e., prior to any ketamine treatment).Predose FQBI scores progressively decreased during maintenancetreatment. After each dose, FQBI scores decreased by ˜50% compared withpredose scores by 1 hour, with no further improvement in score at 2hours. See FIG. 14.

Example 4

The effect of the R-107 tablets (See Example 1) on avoidance and anxietyratings in patients with a DSMS specific phobia, spider phobia isevaluated. In this study, participants with DSMS spider phobia areassessed initially via scores on a Fear of Spiders Questionnaire (FSQ;Symanski and O'Donohue 1995; minimum score 95) and performance in aBehavioural Avoidance Task (BAT; Garcia-Palacios et al 2002; maximumscore 3). Patients with FSQ scores ≥95 demonstrate high phobic anxietyrelating to spiders, and BAT scores ≤3 indicate high levels of phobicavoidance. After completing this testing, participants receive singledoses of either R-107 tablets 120 mg or matching placebo tablets, underdouble-blind randomized conditions. Three hours later, patients againcomplete FSQ and BAT testing. Participants randomized to R-107 tabletsreport lower FSQ scores, and increased BAT scores compared with thoserandomized to placebo, indicating reduced phobic anxiety and avoidance.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A method of treating a patient fortreatment-resistant depression; treatment-resistant anxiety, includingbut not limited to DSM-V Generalized Anxiety Disorder, Social AnxietyDisorder, Panic Disorder, Post-Traumatic Stress Disorder, and/orObsessive-Compulsive Disorder; or DSM-5 Specific Phobia comprising:selecting a patient in need of such treatment; and orally administeringto the patient a tablet comprising: (A) a core comprising: i) atherapeutically effective amount of an active agent selected from thegroup consisting of ketamine, norketamine, pharmaceutically acceptablesalts thereof, and combinations thereof; ii) at least one high molecularweight polyethylene oxide (PEO) that is cured, wherein said highmolecular weight PEO has an approximate molecular weight of from about 2million to about 7 million, based upon rheological measurements, and ispresent in an amount of at least about 30% (by weight) of the core; (B)a coating on said core, wherein said tablet is crush resistant and has abreaking strength of at least about 200 N; and provides apharmacokinetic parameter selected from the group consisting of aketamine Cmax between about 12 and about 42 ng/mL; a ketamine AUC0-infbetween about 79 and about 385 ng·h/mL; a norketamine Cmax between about74 and about 315 ng/mL; a norketamine AUC_(0-inf) between about 872 andabout 4079 ng·h/mL after administration of a single tablet to a patient,wherein the tablet treats the symptoms of said treatment-resistantdepression; treatment-resistant anxiety, including but not limited toDSM-V Generalized Anxiety Disorder, Social Anxiety Disorder, PanicDisorder, Post-Traumatic Stress Disorder, and/or Obsessive-CompulsiveDisorder; or DSM-5 Specific Phobia.
 2. The method of claim 1 wherein themolecular weight of said high molecular weight PEO is selected from thegroup consisting of at least about 2,000,000, at least about 4,000,000;at least about 5,000,000; at least about 6,000,000; and at least about7,000,000.
 3. The method of claim 1 wherein the active agent comprisesat least about 1% (by weight) of the core.
 4. The method of claim 1wherein said high molecular weight PEO comprises at least about 50% (byweight) of said core.
 5. The method of claim 1 wherein the dosage amountof active agent is selected from the group consisting of about 1 mg,about 2 mg, about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 120mg, and about 240 mg.
 6. The method of claim 1 wherein the tablet iscured at a temperature of about 70° C. to about 75° C.
 7. The method ofclaim 1 wherein the coating comprises: i) hydroxypropylmethylcellulose;ii) titanium dioxide; and iii) polyethylene glycol.
 8. The method ofclaim 1 wherein the mean tmax of said active agent is selected from thegroup consisting of at least about 4 hours, at least about 6 hours, atleast about 8 hours, at least about 10 hours, at least about 11 hours,and at least about 12 hours.
 9. The method of claim 1 wherein the tabletis suitable for once weekly, twice weekly, three times weekly, oncedaily or twice daily administration to a patient.
 10. The method ofclaim 1 wherein the symptoms of said treatment-resistant depression orsaid anxiety or said phobia are measurably alleviated within about 1-3or about 2 hours of oral administration of said active agent.
 11. Themethod of claim 1 wherein said method comprises oral administration of asingle dose of said active agent.
 12. The method of claim 1 wherein saidmethod comprises oral administration of multiple doses of said activeagent.
 13. The method of claim 1 wherein a single oral administration ofsaid active agent in doses between 30-180 mg is sufficient to alleviatethe effects of said depression or said anxiety or said phobia for 3-7days.
 14. The method of claim 1 wherein said tablet has no or minimaldissociative side effects in the patient.
 15. The method of claim 1wherein maximal mean improvements in ratings of depressed mood occurafter approximately 6 weeks of maintenance treatment.
 16. The method ofclaim 1 wherein maximal mean improvements in ratings of anxious moodoccur after approximately 2 weeks of maintenance treatment.
 17. Themethod of claim 1 wherein the DSM-5 Specific Phobia is selected from thegroup consisting of environmental phobia, animal phobia, situationalphobia, bodily phobia, and combinations thereof.
 18. The method of claim21, wherein the environmental phobia is selected from the groupconsisting of fear of germs, deep water, heights, other environmentalphobias, and combinations thereof; the animal phobia is selected fromthe group consisting of fear of dogs, spiders, snakes, other animalphobias, and combinations thereof; wherein the situational phobia isselected from the group consisting of fear of flying in an aeroplane,visiting the dentist, other situational phobias, and combinationsthereof; or the bodily phobia is selected from the group consisting offear of blood exposure, other bodily phobias, and combinations thereof.19. The method of claim 1 further comprising administering apharmaceutically effective dose of a second or additional agent, whereinsaid second or additional agent has antidepressant properties.
 20. Themethod of claim 1 wherein said method further comprises an additionaltherapy selected from: at least one antidepressant selected from thegroup consisting of citalopram, escitalopram oxalate, fluoxetine,fluvoxamine, paroxetine, sertraline, dapoxetine; venlafaxine andduloxetine; harmaline, iproniazid, isocarboxazid, nialamide, pargyline,phenelzine, selegiline, toloxatone, tranylcypromine, brofaromine,moclobemide; amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dibenzepin, dothiepin, doxepin, imipramine, iprindole,lofepramine, melitracen, nortriptyline, opipramol, protriptyline,trimipramine; maprotiline, mianserin, nefazodone, trazodone,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one mood stabilizer selected from the group consisting of lithiumcarbonate, lithium orotate, lithium salt, valproic acid, divalproexsodium, sodium valproate, lamotrigine, carbamazepine, gabapentin,oxcarbazepine, topiramate, pharmaceutically acceptable salts, isomers,and combinations thereof; at least one herbal antidepressants selectedfrom the group consisting of St John's Wort; kava kava; echinacea; sawpalmetto; holy basil; valerian; milk thistle; Siberian ginseng; Koreanginseng; ashwagandha root; nettle; Ginkgo biloba; gotu kola; ginkgo/gotukola supreme; astragalus; goldenseal; dong quai; ginseng; St. John'swort supreme; echinacea; bilberry, green tea; hawthorne; ginger, gingko,turmeric; boswellia serata; black cohosh; cats claw; catnip; chamomile;dandelion; chaste tree berry; black elderberry; feverfew; garlic; horsechestnut; licorice; red clover blossom and leaf Rhodiola Rusa; Coleusforskohlii; Passion Flower; eyebright; yohimbe; blueberry plant; blackpepper plant; Hydrocotyle asiatica; astragalus; valerian poppy root andgrape seed; vervain; echinacea ang root; Skull Cap; serenity elixir; andcombinations thereof; at least one antipsychotic agent selected from thegroup consisting of haloperidol, chlorpromazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, trifluoperazine,mesoridazine, promazine, triflupromazine, levomepromazine, promethazine,chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine,olanzapine, risperidone, quetiapine, ziprasidone, amisulpride,paliperidone, dopamine, bifeprunox, norclozapine, aripiprazole,tetrabenazine, cannabidiol, pharmaceutically acceptable salts, isomers,and combinations thereof; at least one serotonin 1a partial agonistselected from the group consisting of buspirone, eltoprazine, ortandospirone, pharmaceutically acceptable salts, isomers, andcombinations thereof; at least one alpha-2-delta ligand selected fromthe group consisting of gabapentin, pregabalin, 3-methylgabapentin,(1alpha,3 alpha,5alpha)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3 aminomethyl-5 methyl-heptanoic acid, (3S,5R)-3 amino-5methyl-heptanoic acid, (3S,5R)-3 amino-5 methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3aminomethyl-5 methyl-octanoic acid, (3S,5R)-3 amino-5 methyl-nonanoicacid, (3S,5R)-3 amino-5 methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, pharmaceuticallyacceptable salts, isomers, and combinations thereof; at least oneantiadrenergic agents selected from the group consisting of clonidine,prazosin, propranolol, fuanfacine, methyldopa, guanabenz; doxazosin,prazosin, terazosin, silodosin, alfuzosin, tamsulosin,dutasteride/tamsulosin, guanadrel, mecemylamine, guanethidine,pharmaceutically acceptable salts, isomers, and combinations thereof; atleast one benzodiazepine agent selected from the group consisting ofalprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam,clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam,nimetazepam, estazolam, flunitrazepam, oxazepam, triazolam,pharmaceutically acceptable salts, isomers, and combinations thereof;other therapeutic interventions selected from the group consisting ofcounseling, psychotherapy, cognitive therapy, electroconvulsive therapy,hydrotherapy, hyperbaric oxygen therapy, electrotherapy and electricalstimulation, transcutaneous electrical nerve stimulation (“TENS”), deepbrain stimulation, vagus nerve stimulation, and transcranial magneticstimulation, and combinations thereof.